US 2005OO74497A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0074497 A1 Schultz (43) Pub. Date: Apr. 7, 2005

(54) HYDROGELS USED TO DELIVER Publication Classification MEDICAMENTS TO THE EYE FOR THE TREATMENT OF POSTERIOR SEGMENT (51) Int. Cl." ...... A61K 39/395; A61K 38/24; DISEASES A61K 31/65; A61K 9/14; A61K 31/56; A61K 31/075 (76) Inventor: Clyde L. Schultz, Ponte Vedra, FL (52) U.S. Cl...... 424/486; 514/8; 514/12; 424/144.1; (US) 514/182; 514/721; 514/152 Correspondence Address: CLARK & ELBING LLP (57) ABSTRACT 101 FEDERAL STREET This invention provides a polymeric drug delivery System BOSTON, MA 02110 (US) including a hydrogel containing one or more drugs for the treatment of a posterior Segment disease. Exemplary drugs (21) Appl. No.: 10/971,997 are anti-angiogenesis compounds for the treatment of macu (22) Filed: Oct. 22, 2004 lar degeneration. Allowing passive transference of this drug from a dilute Solution into the hydrogel produces the deliv Related U.S. Application Data ery System. The hydrogel, when placed in contact with the eye, delivers the drug. The delivery of the drug is Sustained (63) Continuation-in-part of application No. 10/821,718, over an extended period of time, which is of particular utility filed on Apr. 9, 2004. in the eye, which is periodically flushed with tears. This Sustained delivery accelerates the treatment process while (60) Provisional application No. 60/461,354, filed on Apr. avoiding potential damaging effects of localized delivery of 9, 2003. high concentrations of compounds, e.g., from eye drops. US 2005/0074497 A1 Apr. 7, 2005

HYDROGELS USED TO DELIVER correcting vision. Such a contact lens may be capable of MEDICAMENTS TO THE EYE FOR THE correcting vision in the range of +8.0 to -8.0 diopters or may TREATMENT OF POSTERIOR SEGMENT be plano. The contact lens may also have a base curve DISEASES between 8.0 and 9.0. 0007. The invention further features a method for making CROSS-REFERENCE TO RELATED a hydrogel drug delivery System by placing the hydrogel, APPLICATIONS e.g., a contact lens, in a Solution containing one or more 0001. This application is a continuation-in-part of U.S. drugs as described herein, which is passively transferred to application Ser. No. 10/821,718, filed Apr. 9, 2004, which the hydrogel. This method may further include the steps of claims benefit of U.S. Provisional Application No. 60/461, Washing the hydrogel in an isotonic Saline Solution and 354, filed Apr. 9, 2003, each of which is hereby incorporated partially desiccating the hydrogel prior to placement in the by reference. Solution. The Solution may have, e.g., a pH between 6.9 and 7.4, and a drug concentration of between 0.00001 and 10%. BACKGROUND OF THE INVENTION In one embodiment, the hydrogel is placed in the Solution of drug for at least 30 minutes. 0002. In general, the invention relates to the fields of hydrogels, drug delivery Systems, and treatment of posterior 0008. In another aspect, the invention features a method Segment diseases. for treating a posterior Segment disease. The method includes placing a hydrogel, as described herein, in contact 0003) Systemic and topical (e.g., via eye drops) admin with an eye, wherein the drug or drugs are passively released istration of drugs for treatment of diseases of the posterior from the hydrogel to treat the disease. In various embodi Segment of the eye, Such as macular degeneration, is often ments, the posterior Segment disease is in the Vitreous, retina undesirable. These methods typically require higher total (e.g., the macula), choroids, Sclera, or optic nerve. The doses of the drug because these routes are inefficient at hydrogel may passively release, for example, at least 0.0001, delivering the drug to the posterior Segment. Such high 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 10, 15, 20, 50, doses increase the cost and may also cause Side effects Such 75, 100, 250, 500, or 1000 tug of a drug, and the hydrogel as local inflammation or adverse Systemic reactions. In may be placed in contact with the eye for at least 0.5, 1, 1.5, addition, for most topical treatments, the drug is quickly 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours. The method washed out of the eye, limiting the effective time of treat for treating a posterior Segment disease, e.g., macular degen ment. eration, may further include the Step of diagnosing the 0004 Thus, Sustained-release delivery devices that con posterior Segment disease prior to placing the hydrogel in tinuously administer a drug to the eye for a prolonged period contact with the eye. of time are desired for the treatment of posterior Segment 0009 Exemplary drugs and posterior segment diseases diseases. are described herein. Preferred drugs include anti-angiogen esis compounds, as described herein, for the treatment of SUMMARY OF THE INVENTION macular degeneration. 0005 The present invention features hydrogel drug deliv 0010. As used herein, by “ambient conditions” is meant ery Systems and methods of producing and using Such room temperature and pressure. Systems for the treatment of disease in the posterior Segment of the eye, e.g., the vitreous, retina (including the macula), 0011. By “existing conditions” is meant in situ in the eye. choroids, Sclera, and optic nerve. The Systems are based on 0012. By “treating” is meant medically managing a a hydrogel into which one or more drugs are passively patient with the intent that a prevention, cure, Stabilization, transferred from a dilute Solution, e.g., an aqueous Solution. or amelioration of the symptoms will result. This term When placed in contact with eye tissue, the drug or drugs includes active treatment, that is, treatment directed Specifi passively transfer out of the hydrogel to provide treatment of cally toward improvement of the disease; palliative treat posterior Segment diseases. ment, that is, treatment designed for the relief of Symptoms 0006 Accordingly, in one aspect, the invention features a rather than the curing of the disease; preventive treatment, polymeric hydrogel that contains a drug for the treatment of that is, treatment directed to prevention of the disease; and a posterior Segment disease, wherein the drug is capable of Supportive treatment, that is, treatment employed to Supple being passively released in a therapeutically effective ment another Specific therapy directed toward the improve amount to treat the posterior Segment disease. Exemplary ment of the disease. The term “treating” also includes hydrogel materials include a tetrapolymer of hydroxymeth Symptomatic treatment, that is, treatment directed toward ylmethacrylate, ethylene glycol, dimethylmethacrylate, and constitutional Symptoms of the disease. methacrylic acid. Other examples of hydrogels include eta 0013 By “ocular environment” is meant the tissues of filcon A, vifilcon A, lidofilcon A, vaSurfilcon A, and poly and Surrounding the eye, including, for example, the Sclera, macon B. In addition, variations of these polymers formed cornea, and other tissues of the ocular cavity and the by the use of different packing Solutions (e.g., phosphate posterior Segment. buffered Saline and boric acid) in the manufacturing process are also included. The hydrogel may be ionic or non-ionic. 0014. The “posterior segment” of the eye includes, with In various embodiments, the drug is capable of being out limitation, the vitreous, retina (including the macula), passively released into the ocular environment under ambi choroids, Sclera, and optic nerve. ent or existing conditions. In other embodiments, the hydro 0015 Exemplary posterior segment diseases include, gel may be shaped as a contact lens, e.g., one capable of without limitation, retinal detachment, diabetic retinopathy, US 2005/0074497 A1 Apr. 7, 2005 macular degeneration (e.g., age-related), proliferative Vit of diopters of +8.0 to -8.0. Exemplary hydrogel contact lens reoretinopathy, endophthalmitis, retinopathy of prematurity, materials include etafilcon A, vifilcon A, lidofilcon A, poly posterior Segment trauma, intraocular lens-related posterior macon B, Vasurfilcon A, and a tetrapolymer of hydroxym Segment complications, retinal vascular diseases, macular ethylmethacrylate, ethylene glycol, dimethylmethacrylate, edema, intraocular tumors, hereditary retinal degenerations, and methacrylic acid. These materials may also be employed AIDS-related retinitis, posterior Segment uveitis, and SyS in other physical forms. Other Suitable hydrogel materials temic diseases with retinal manifestations. For the purposes are known to those skilled in the art. The hydrogels may be of this invention, glaucoma is not a posterior Segment insoluble, may absorbable (e.g., dissolve or degrade) over disease. time in Vivo, e.g., Over one day, one week, one month, Six months, or one year or more, or may be partially Soluble and 0016 All percentages described in the present invention partially insoluble. The drug is passively delivered, for are by weight unless otherwise Specified. example, by diffusion out of the hydrogel, by desorption 0.017. Other features and advantages of the invention will from the hydrogel, or by release as the hydrogel dissolves. be apparent from the following description and the claims. Exemplary Soluble materials include a copolymer of trim ethylene carbonate and polyglycolicacid (e.g., Maxon), DETAILED DESCRIPTION OF THE polyglactin 910 (e.g., Vicryl), glyconate (e.g., MonoSyn), INVENTION poly-p-dioxanone (e.g., Monoplus), polyglycolic acid (e.g., Safil), polyglycolic acid felt (e.g., NeoVeil), poly-4-hydroxy 0.018. This invention provides a polymeric drug delivery butyrate, combinations of poly(L-lactide) and poly(L-lac System including a hydrogel containing one or more drugs tide-co-glycolide), glycol methacrylate, poly-DL-lactide, for the treatment of a posterior Segment disease. Allowing and Primacryl (Johnson & Johnson, e.g., Craniosorb AFS). passive transference of this drug from a dilute Solution into Exemplary materials that are partially Soluble or degradable the hydrogel produces the delivery System. The hydrogel, include a composite mesh of oxidized regenerated cellulose, when placed in contact with the eye, delivers the drug. The polypropylene, and polydioxanone (e.g., Proceed Mesh delivery of the drug is Sustained over an extended period of from Ethicon) and a mesh of polypropylene (prolene) and time, which is of particular utility in the eye, which is poligelcaprone (Monocryl) (e.g., Ultrapro from Ethicon). periodically flushed with tears. This sustained delivery may accelerate the treatment process while avoiding potential 0023 The drug delivery system may be produced from a damaging effects of localized delivery of high concentra partially desiccated hydrogel (or equivalently a partially tions of drugs compared, e.g., to eye drops. hydrated hydrogel). The desiccation step removes, for example, approximately 5%, 10%, 15%, 20%, 25%, 30%, 0019 Posterior Segment Diseases 40%, 50%, 60%, or 75% of the water in the hydrogel. 0020 Posterior segment diseases to be treated by the Desiccation can occur, for example, by exposure of the present invention include, for example, retinal detachment, hydrogel to ambient or humidity controlled air, by heating neovascularization, diabetic retinopathy, macular degenera the hydrogel for a specific period of time, or by blowing tion (e.g., age-related), proliferative vitreoretinopathy, dried gas, Such as N2, over the hydrogel. In one embodiment, endophthalmitis, retinopathy of prematurity, posterior Seg the hydrogel is Saturated with physiological (isotonic) Saline ment trauma, intraocular lens-related posterior Segment prior to desiccation. The partially desiccated hydrogel is complications, retinal vascular diseases, macular edema then Soaked, e.g., for at least 30 minutes, in a dilute Solution (e.g., diabetic), intraocular tumors, retinal degeneration of drug, e.g., at a pH between 6.9 to 7.4. In certain embodi (e.g., hereditary), vascular retinopathy, inflammatory dis ments, the drug is transferred to a contact lens from a eases of the retina, AIDS-related retinitis, uveitis, and SyS non-aqueous Solvent, e.g., dimethyl Sulfoxide, which may be temic diseases with retinal manifestations. Neovasculariza at least partially removed and replaced with an aqueous tions include retinal, choroidal, and Vitreal. The retinal Solution prior to use in a patient. The hydrogels may also be neovascularization to be treated can be caused by diabetic Soaked in drug Solution for at least 1 hour, 6 hours, 12 hours, retinopathy, vein occlusion, Sickle cell retinopathy, retinopa or 24 hours. The concentration of drug into which the thy of prematurity, retinal detachment, ocular ischemia, or hydrogel is placed is typically 0.000001, 0.000005, 0.00001, trauma. The intravitreal neovascularization to be treated can 0.00005, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, be caused by diabetic retinopathy, vein occlusion, Sickle cell 1, 5, 10, 15, 20, 50, 75, 100, 250, 500, or 1000 ug/mL. retinopathy, retinopathy of prematurity, retinal detachment, Higher concentrations may also be used, for example, to ocular ischemia, or trauma. The choroidal neovasculariza reduce the Soaking time. The drug is passively transferred tion to be treated can be caused by retinal or Subretinal into the hydrogel. This transfer may occur at least in part by disorders of age-related macular degeneration, diabetic rehydrating the hydrogel. Diffusion of the drug into the macular edema, presumed ocular histoplasmosis Syndrome, water or polymer in the hydrogel may also occur. In alter myopic degeneration, angioid streaks, or ocular trauma. native embodiments, a fully hydrated or fully desiccated Other posterior Segment diseases are known in the art. hydrogel is placed in the Soaking Solution to produce the medicated hydrogel. 0021 Drug Delivery System 0024. Desirably, the concentration of drug transferred to 0022 Hydrogels. This invention may employ different the hydrogel is substantially lower than the solution in which polymer compositions. For example, conventional Soft con the hydrogel is Soaked. For example, the concentration of tact lenses can be used and can be either ionic or non-ionic growth factor in the hydrogel is at least 2x, 5x, or 10x leSS hydrogels containing between 10% and 90%, e.g., 24% or than that of the Soaking Solution. Some drugs, however, may 37.5% to 65% or 75%, water by weight and can have any have a higher affinity for a hydrogel than the Soaking base curve, e.g., from 8.0 to 9.0. The contact lenses may also Solution, and Such a hydrogel will have a higher concentra have the ability to correct vision, for example, over a range tion of drug than the Solution in which it was Soaked, e.g., US 2005/0074497 A1 Apr. 7, 2005

at least 2x, 5x, or 10x more. The water content and type of Sterone, flutamide, foScamet, fumagillin analogs, fuisidic hydrogel, time and conditions, e.g., temperature of Soaking, acid, ganciclovir, gemcitabine HCL, gemtuzumab ozogami composition of the Soaking Solution (e.g., ionic strength and cin, gentamicin, glipizide, glutathione, glyburide, goserelin, pH), and type of drug employed also may influence the gramicidin, heat shock proteins, heparin, herbimycon A, concentration of drug in the drug delivery System. Since the homatropine, humanized anti-IL-2receptor mAb (Dacli water content of the hydrogel may also help to determine the Zumab), hydrocortisone, hydroxyamphetamine, hydrox total amount of drug present in a hydrogel, it represents a yurea, idoxuridine, ifosfamide, imidazole-based antifungals, variable by which to control the amount of drug delivered to insulin, interferon alfa-2a, interferon-gamma, interferons, a tissue. The production of a hydrogel containing a Specified interleukin-2, irinotecan HCL, ketoconazole, leflunomide, amount of drug can be accomplished by routine experimen letrozole, leuprolide, levamisole, lidocaine, lipid formula tation by one skilled in the art. tions of antifungals, liposomalamphotericin B, lomustine, macrollide immunosuppressants, matrix metalloproteinase 0.025 Drugs for the Treatment of Posterior Segment inhibitors, medroxyprogesterone, medrySone, melphalan, Diseases. memantine, mercaptopurine, mestranol, metals (e.g., cobalt 0026. Any drug for the treatment of a posterior segment and copper), methapyriline, methazolamide, methotrexate, disease may be included in a drug delivery System described methylprednisolone, minocycline, mitomycin, mitotane, herein. Classes of drugs include anti-infectives (e.g., anti mitoxantrone hydrochloride, mono and polyclonal antibod biotics, antibacterial agents, antiviral agents, and antifungal ies, muramyl dipeptide, mycophenolate mofetil, naphazo agents); analgesics, anesthetics, antiallergenic agents; mast line, neomycin, nepafenac, neuroimmunophilin ligands, cell Stabilizers, Steroidal and non-Steroidal anti-inflamma neurotrophic receptorS(Aktkinase), neurotropins, nicotina tory agents, decongestants, antioxidants, nutritional Supple mide (vitamin B3), nimodipine, nitrofurazone, nitrogen ments, angiogenesis inhibitors, antimetabolites, fibrinolyt mustard, nitrosoureas, norethynodrel, NOS inhibitors, ics; neuroprotective drugs, angiostatic Steroids, mydriatics, Ondansetron, oprelvekin, oraptamers, oxytetracycline, pacli cyclopegic mydriatics, miotics, vasoconstrictors, vasodila taxel, pentostatin, pheniramine, phenylephrine, phospholi tors, anticlotting agents, anticancer agents, antisense agents, neiodine, pilocarpine, pipobroman, platelet factor 4, plati immunomodulatory agents, carbonic anhydrase inhibitors, num coordination complexes (Such as cisplatin and integrin antagonists, cyclooxgenase inhibitors, differentia carboplatin), plicamycin, polymyxin, prednisolone, pred tion modulator agents, Sympathomimetic agents, VEGF nisone, procarbazine, tacrolimus, prophenpyridamine, pros antagonists; immunosuppresant agents, and combinations taglandins, protamine, protease and integrase inhibitors, and prodrugs thereof Other Suitable drugs are known in the pyrilamine, rapamycin, ribavirin, rimeXolone, rituximab, art. SargramoStim, Scopolamine, Sodium propionate, Streptozo cin, Succinic acid, Sulfacetamide, Sulfamethizole, Sulfona 0.027 Exemplary drugs include 17-ethynylestradiol, mides, Sulfoxazole, Superoxide dismutase, Suramine, tamox 2-ethoxy-6-Oxime-estradiol, 2-hydroxyestrone, 2-propenyl ifen, temozolomide, teniposide, tetracycline, estradiol, 2-propynl-estradiol, 4.9(11)-pregnadien-17C,21 tetrahydrazoline, thalidomide, thioguanine, thymopentin, diol-3,20-dione, 4.9(11)-pregnadien-17C,21-diol-3,20-di thyroid hormones, tolaZamide, tolbutamide, topotean hydro one-21-acetate, 4-methoxyestradiol, 5-fluorouracil, chloride, toremifene citrate, transforming factor beta2, tras 6-mannosephosphate, acetazolamide, acetohexamide, ace tuZumab, triamcinolone, triazole antifungals, trifluorothymi tylcholinesterase inhibitors, acyclovir, adrenal cortical dine, triptorelinpamoate, triSodium phosphonoformate, Steroids, adriamycin, aldesleukin, aldose reductase inhbi tors, alkylating agents including cyclophosphamide, alpha tropicamide, tumor necrosis factor, uracil mustard, valrubi tocopherol, amifostine, amphotericin B, anastrozole, cin, VEGF antagonists (e.g., VEGF antibodies and VEGF anecortave acetate, angiostatic Steroids, angiostatin, antaZO antisense), Vidarabine, vinblastine, Vincristine, Vindesine, line, anthracycline antibiotics, antibody to cytokines, anti Vitamin B12 analogues, and Voriconazole. clotting activase, anti-cytomegalovirus agents, antifibrino 0028. In one embodiment, the drug is an anti-angiogen gen, antineogenesis proteins, arsenic trioxide, asparaginase, esis compound, e.g., for treatment of macular degeneration. atenolol, atropine Sulfate, azacytidine, azathioprine, AZT, Anti-angiogenesis compounds may exert their effects by any bacitracin, bacitracin, betamethasone, betaxolol, beXaroteine, mechanism, including metalloproteinase inhibitors, mono bleomycin, buSulfan, calcium channel antagonists (e.g., clonal antibodies (e.g., anti-integrin or anti-VEGF antibod imodipine and diltiazem), capecitabine, carbachol, carmus ies), calcium channel inhibitors, vascular targeting agents, tine, cephalosporin antibiotics, chlorambucil, chlorampheni tetracycline derivatives, PKC inhibitors, IP-10 upregulators, col, chlorpheniramine, chlorpropamide, chlortetracycline, growth factor antagonists, PDGF antagonists, VEGF colchicine, cyclooxgenase II inhibitors, cyclopentolate, antagonists, cytotoxics, antiproliferatives, and Na or Ca cyclophosphamide, cyclosporine, cycloSporine A, cytara channel blockers. Exemplary anti-angiogenesis compounds bine, cytochalasin B, cytokines, dacarbazine, dactinomycin, include 2-methoxyestradiol (PANZEM) (EntreMed), A6, daunorubicin, demecarium bromide, dexamethasone, ABT-510, ABX-IL8 (Abgenix), actimid, Ad5FGF-4 (Col diamox, dichlorphenamide, didanosine, dihydroxylipoic lateral Therapeutics), AG3340 (Agouron Pharmaceuticals acid, diisopropylfluorophosphate, docetaxel, echinocandin Inc. LaJolla, Calif.), alpha5beta1 integrin antibody, like lipopeptide antibiotics, echothiophateiodide, eliprodil, AMG001 (AnCes/Daichi Pharmaceuticals), anecortave endostatin, epinephrine, epirubicin hydrochloride, erythro acetate (Retaane, Alcon), angiocol, angiogenix (Endovasc mycin, erythropoietin, eSerine Salicylate, estradiol, estra Ltd), angiostatin (EntreMed), angiozyme, antiangiogenic mustine, etanercept, ethisterone, etoposide, etoposide phos antithrombin 3 (Genzyme Molecular Oncology), anti-VEGF phate, etretinate, eucatropine, exemestrane, famvir, (Genentech), anti-VEGF Mab, aplidine, aptosyn, ATN-161, fibrinolysin, filgrastim, floxuridine, fluconazole, fludarabine, avastin (bevacizumab), AVE8062A, Bay 12-9566 (Bayer fluocinolone, fluoromethalone, fluoroquinolone, fluoxyme Corp. West Haven, Conn.), benefin, BioBypass CAD US 2005/0074497 A1 Apr. 7, 2005

(VEGF-121) (GenVec), MS275291, CAI (carboxy-amido pha), leptin, vascular endothelial growth factor (VEGF)/ imidazole), carboxymidotriazole, CC 4047 (Celgene), CC vascular permeability factor (VPF), midkine, and progranu 5013 (Celgene), CC7085, CDC 801 (Celgene), Celebrex lin. (Celecoxib), CEP-7055, CGP-41251/PKC412, cilengitide, 0029. A drug may be admixed with a pharmaceutically CM101 (Carborned Brentwood, Tenn.), col-3 (CollaGeneX acceptable carrier adapted to provide Sustained release of the Pharmaceuticals Inc. Newton, Pa.), combretastatin, combre drug. Exemplary carriers include emulsions, Suspensions, tastatin A4P (Oxigene/Bristol-Myers Squibb), CP-547, 632, polymeric matrices, microSpheres, microcapsules, micropar CP-564,959, Del-1 (VLTS-589) (Valentis), dexrazoxane, ticles, liposomes, lipospheres, hydrogels, Salts, and poly didemnin B, DMXAA, EMD 121974, endostatin mers with the drug reversibly bound electroStatically, chemi (EntreMed), FGF (AGENT 3) (Berlex (Krannert Institute of cally, or by entrapment. A pharmaceutically acceptable Cardiology)), flavopiridol, GBC-100, genistein concentrated carrier may also include a transScleral diffusion promoting polysaccharide, green tea extract, HIF-1alpha (Genzyme), agent, Such as dimethylsulfoxide, ethanol, dimethylforma human chorio-gonadotrophin, IM862 (Cytran), INGN 201, mide, propylene glycol, N-methylpyrolidone, oleic acid, interferon alpha-2a, interleukin-12, iressa, ISV-120 (Batim isopropyl myristate, polar aprotic Solvents, polar protic astat), LY317615, LY-333531 (Eli Lilly and Company), Mab Solvents, Steroids, Sugars, polymers, Small molecules, huJ591-DOTA-90 Yttrium (90Y), marimastat (British Bio charged Small molecules, lipids, peptides, proteins, and tech Inc. Annapolis, Md.), Medi-522, metaret (Suramin), Surfactants. neoretna, neovastat (AEtema Laboratories), NM-3, NPe6, 0030 The use of preservatives is non-ideal as they may NV1 FGF (Gencell/Aventis), octreotide, oltipraz, paclitaxel transfer to a hydrogel at a disproportionately high concen (e.g., taxol, docetaxel, or paxene), pegaptainib Sodium (Eye tration and cause cytotoxicity. tech), penicillamine, pentosan polysulphate, PI-88, prinom astat (Agouron Pharmaceuticals), PSK, psorvastat, PTK787/ 0031 Treatment Approaches ZK222584, ranibizumab (Lucentis, Genentech), razoxane, 0032) To treat a posterior segment disease, the hydrogels replistatatin (Platelet factor-4), revimid, RhuMab, of the invention are contacted with the ocular fluid of an Ro317453, squalamine (Magainin Pharmaceuticals, Inc. individual. The hydrogels may be employed in an open or Plymouth Meeting, Pa.), SU101 (Sugen Inc. Redwood City, closed eye period. When the System is shaped as a contact Calif.), SU11248, SU5416 (Sugen), SU6668 (Sugen), lens, the lens may simply be placed in the eye normally in tamoxifen, tecogalan Sodium, temptostatin, tetrathiomol, order to deliver the drug. The hydrogel may also be part of a bandage or may be adhered (e.g., by adhesives or Sutures) tetrathiomolybdate, thalidomide (EntreMed Inc., Rockville, to the eye. If the hydrogel is placed internally in a patient, Md.), thalomid, TNP-470 (TAP Pharmaceuticals Inc. Deer the hydrogel is advantageously biodegradable. The time field, Wis.), UCN-01, VEGF (Genentech Inc. South San period over which the lenses are worn may depend on the Francisco, Calif.), VEGF trap, Vioxx, vitaxin (Ixsys Inc. San level of treatment desired or the amount of drug in the lens. Diego, Calif.), vitaxin-2 (MedImmune), ZD6126, and Hydrogels may be considered to be disposable and may be ZD6474. Additionally anti-angiogensis compounds found in replaced after a specified period of time, e.g., at least 0.5, 1, Vivo and Suitable for use in the compositions and methods 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours. described herein include angiostatin (plasminogen frag Alternatively, a hydrogel that has a depleted amount of drug ment), metalloproteinase inhibitors (TIMPs), antiangiogenic may be recycled by Soaking the hydrogel again in a Solution antithrombin III (aa ATIII), pigment epithelial-derived factor of drug. (PEDF), canstatin, placental ribonuclease inhibitor, carti 0033. The methods of treatment described herein are lage-derived inhibitor (CDI), plasminogen activator inhibi capable of delivering a drug to the ocular environment of a tor, CD59 complement fragment, platelet factor-4 (PF4), patient for a period of time longer than the dwell time endostatin (collagen XVIII fragment), prolactin 16kD frag achievable by gels or drops. The convenience and Simplicity ment, fibronectin fragment, proliferin-related protein, gro of this System would in many cases enhance patient com beta, retinoids, heparinases, tetrahydrocortisol-S, heparin pliance with therapy. hexasaccharide fragment, thrombospondin-1, human chori onic gonadotropin (hCG), transforming growth factor-beta, 0034). In certain embodiments, at least 0.001, 0.005, 0.01, interferon alpha/beta/gamma, tumistatin, interferon induc 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 50, 75, 100, 200, 500, 750, ible protein (IP-10), vasculostatin, interleukin-12 (IL-12), or 1000 tug of the drug is released from the hydrogel. This vasostatin (calreticulin fragment), kringle 5 (plasminogen delivery occurs by passive transfer and allows medications fragment), angioarrestin, and 2-methoxyestradiol. Further to be released into the ocular fluid. The use of hydrogels of more compounds that inhibit, block, or antagonize the the invention may also allow patients to be treated using angiogenic activity of the following Species in Vivo are fewer applications than with traditional methods. In addi uSeable in the methods and compositions described herein: tion, the drug may be released from the hydrogel at a more angiogenin, placental growth factor, angiopoietin-1, plate rapid rate than the release of the drug into a fixed volume of let-derived endothelial cell growth factor (PD-ECGF), Del fluid because as the eye produces tears, the drug released is 1, platelet-derived growth factor-BB (PDGF-BB), fibroblast flushed away from the site of application causing an increase growth factors: acidic (aFGF) and basic (bFGF), pleiotro in the relative rate of diffusion of the drug out of the phin (PTN), follistatin, proliferin, granulocyte colony hydrogel. The replenishing action of fluids Such as tears may Stimulating factor (G-CSF), transforming growth factor also effectively increase the rate of diffusion of the drug into alpha (TGF-alpha), hepatocyte growth factor (HGF)/scatter the fluid and lead to earlier onset of therapeutic activity. factor (SF), transforming growth factor-beta (TGF-beta), 0035) In one embodiment, the drug will penetrate the interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-al ocular tissue and migrate into the aqueous humor of the eye. US 2005/0074497 A1 Apr. 7, 2005

Over time, the concentration of the drug will increase Such 6. The polymeric hydrogel of claim 1, wherein Said that ocular tissue in the posterior Segment of the eye will anti-angiogenesis compound is an anti-VEGF antibody. come into contact with the drug. The drug may have effects 7. The polymeric hydrogel of claim 1, wherein said on other types of Structures, cells, or tissues that may be anti-angiogenesis compound is angiostatin (plasminogen present at the time of or prior to administration of the drug. fragment), a TIMPs, antiangiogenic antithrombin III, pig ment epithelial-derived factor (PEDF), canstatin, placental 0036). Other Embodiments ribonuclease inhibitor, cartilage-derived inhibitor (CDI), 0037 Modifications and variations of the described plasminogen activator inhibitor, CD59 complement frag methods of the invention will be apparent to those skilled in ment, platelet factor-4, endostatin (collagen XVIII frag the art without departing from the Scope and Spirit of the ment), prolactin 16kD fragment, fibronectin fragment, pro invention. Although the invention has been described in liferin-related protein, gro-beta, a retinoid, a heparinase, connection with Specific desirable embodiments, it should tetrahydrocortisol-S, heparin hexasaccharide fragment, be understood that the invention as claimed should not be thrombospondin-1, human chorionic gonadotropin, trans unduly limited to Such specific embodiments. Indeed, vari forming growth factor-beta, interferon alpha, interferon ous modifications of the described modes for carrying out beta, or interferon gamma, tumistatin, interferon inducible the invention, which are obvious to those skilled in the art, protein, vasculostatin, interleukin-12, vasostatin (calreticu are intended to be within the scope of the invention. lin fragment), kringle 5 (plasminogen fragment), angioar restin, or 2-methoxyestradiol. 0.038. Other embodiments are within the claims. 8. The polymeric hydrogel of claim 1, wherein said What is claimed is: anti-angiogenesis compound is an inhibitor or antagonist of 1. A polymeric hydrogel comprising an anti-angiogenesis angiogenin, placental growth factor, angiopoietin-1, plate compound for the treatment of a posterior Segment disease, let-derived endothelial cell growth factor, Del-1, platelet wherein Said anti-angiogenesis compound is capable of derived growth factor-BB, aFGF, bFGF, pleiotrophin, fol being passively released from Said polymeric hydrogel in a listatin, proliferin, granulocyte colony-Stimulating factor, therapeutically effective amount to treat Said posterior Seg transforming growth factor-alpha, hepatocyte growth factor, transforming growth factor-beta, interleukin-8, tumor necro ment disease. sis factor-alpha, leptin, vascular endothelial growth factor, 2. The polymeric hydrogel of claim 1, wherein Said midkine, or progranulin. hydrogel has a water content of between 10% and 90%. 9. The polymeric hydrogel of claim 1, wherein said 3. The polymeric hydrogel of claim 2, wherein said hydrogel comprises a tetrapolymer of hydroxymethyl hydrogel has a water content of between 37.5% and 75%. methacrylate, ethylene glycol, dimethylmethacrylate, and 4. The polymeric hydrogel of claim 1, wherein Said anti-angiogenesis compound is a metalloproteinase inhibi methacrylic acid. tor, monoclonal antibody, calcium channel inhibitor, Vascu 10. The polymeric hydrogel of claim 1, wherein said drug lar targeting agent, tetracycline derivative, PKC inhibitor, is capable of being passively released into an ocular envi IP-10 upregulator, growth factor antagonist, PDGF antago ronment under ambient conditions. nist, VEGF antagonist, cytotoxic, antiproliferative, or 11. The polymeric hydrogel of claim 1, wherein Said drug Sodium channel blocker. is capable of being delivered to the posterior Segment of the 5. The polymeric hydrogel of claim 1, wherein said eye. anti-angiogenesis compound is 2-methoxyestradiol, A6, 12. The polymeric hydrogel of claim 1, wherein Said drug ABT-510, ABX-IL8, actimid, Ad5FGF-4, AG3340, is capable of being delivered to the macula or retina. alpha5beta1 integrin antibody, AMG001, anecortave 13. The polymeric hydrogel of claim 1, wherein Said drug acetate, angiocol, angiogenix, angiostatin, angiozyme, anti is capable of being passively released into an ocular envi angiogenic antithrombin 3, anti-VEGF, anti-VEGF Mab, ronment under existing conditions. aplidine, aptosyn, ATN-161, avastin, AVE8062A, Bay 14. The polymeric hydrogel of claim 1, wherein said 12-9566, benefin, BioBypass CAD, MS275291, CAI, car hydrogel is shaped as a contact lens. boxymidotriazole, CC 4047, CC 5013, CC7085, CDC801, 15. The polymeric hydrogel of claim 14, wherein said Celebrex, CEP-7055, CGP-41251/PKC412, cilengitide, hydrogel is capable of correcting vision. CM101, col-3, combretastatin, combretastatin A4P, CP-547, 16. The polymeric hydrogel of claim 15, wherein said 632, CP-564, 959, Del-1, dexrazoxane, didemnin B, hydrogel is capable of correcting vision in the range of +8.0 DMXAA, EMD 121974, endostatin, FGF (AGENT 3), to -8.0 diopters. flavopiridol, GBC-100, genistein concentrated polysaccha 17. The polymeric hydrogel of claim 14, wherein said ride, green tea extract, HIF-1alpha, human chorio-gonadot hydrogel has a base curve between 8.0 and 9.0. rophin, IM862, INGN 201, interferon alpha-2a, interleukin 18. The polymeric hydrogel of claim 1, wherein said 12, iressa, ISV-120, LY317615, LY-333531, Mab hull 591 hydrogel comprises an ionic polymer. DOTA-90 Yttrium, marimastat, Medi-522, metaret, 19. The polymeric hydrogel of claim 1, wherein said neoretna, neovastat, NM-3, NPe6, NV1 FGF, octreotide, hydrogel comprises a non-ionic polymer. oltipraz, paclitaxel, pegaptainib Sodium, penicillamine, pen 20. The polymeric hydrogel of claim 1, wherein said tosan poly Sulphate, PI-88, prinomastat, PSK, pSorvastat, hydrogel comprises etafilcon A, vifilcon A, polymacon B, PTK787/ZK222584, ranibizumab, razoxane, replistatatin, lidofilcon A, or Vasurfilcon A. revimid, RhuMab, Ro317453, squalamine, SU101, 21. The polymeric hydrogel of claim 1, wherein Said SU 11248, SU5416, SU6668, tamoxifen, tecogalan Sodium, hydrogel is at least partially absorbable in Vivo. temptostatin, tetrathiomol, tetrathiomolybdate, thalidomide, 22. The polymeric hydrogel of claim 21, wherein Said thalomid, TNP-470, UCN-01, VEGF, VEGF trap, Vioxx, hydrogel comprises a copolymer of trimethylene carbonate vitaxin, vitaxin-2, ZD6126, or ZD6474. and polyglycolicacid, polyglactin 910, glyconate, poly-p- US 2005/0074497 A1 Apr. 7, 2005

dioxanone, polyglycolic acid, polyglycolic acid felt, poly 25. The method of claim 24, wherein said posterior 4-hydroxybutyrate, a combination of poly(L-lactide) and Segment disease is macular degeneration. poly(L-lactide-co-glycolide), glycol methacrylate, poly-DL 26. The method of claim 24, wherein Said anti-angiogen lactide, or Primacryl. esis compound is an anti-VEGF antibody. 23. The polymeric hydrogel of claim 21, wherein said hydrogel comprises a composite of oxidized regenerated 27. A method of fabricating a polymeric hydrogel, Said cellulose, polypropylene, and polydioxanone or a composite method comprising the Steps of contacting Said polymeric of polypropylene and poligelcaprone. hydrogel with a Solution of an anti-angiogenesis compound 24. A method of treating a posterior Segment disease, Said capable of treating a posterior Segment disease, wherein Said method comprising contacting an eye of a Subject with the anti-angiogenesis compound is passively transferred into hydrogel of claim 1, wherein Said hydrogel delivers to Said Said hydrogel. eye a therapeutically effective amount of an anti-angiogen esis compound.