Sustained release intraocular implants and methods for treating ocular vasculopathies

Abstract

Biocompatible intraocular implants include an alpha-2 adrenergic receptor agonist and a polymer associated with the alpha-2 adrenergic receptor agonist to facilitate release of the alpha-2 adrenergic receptor agonist into an eye for an extended period of time. The alpha-2 adrenergic receptor agonist may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. The implants may be placed in an eye to treat one or more ocular conditions, such as an ocular vasculopathy or glaucoma, among others.

1 . A biodegradable intraocular implant comprising: 
 an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer matrix that releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for a time effective to reduce ocular vascular occlusion in an eye in which the implant is placed, the time being at least about one week after the implant is placed in the eye.    
     
     
         2 . The implant of  claim 1 , wherein the alpha-2 adrenergic agonist is selected from the group consisting of quinoxalines, (2-imidozolin-2-ylamino)quinoxalines, 5-bromo-6-(2-imidozolin-2-ylamino)quinoxalines, derivatives thereof and mixtures thereof.  
     
     
         3 . The implant of  claim 1 , wherein the alpha-2 adrenergic agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.  
     
     
         4 . The implant of  claim 1 , wherein the alpha-2 adrenergic agonist is brimonidine tartrate.  
     
     
         5 . The implant of  claim 4 , further comprising a preservative.  
     
     
         6 . The implant of  claim 5 , wherein the preservative is a purite.  
     
     
         7 . The implant of  claim 1 , further comprising an additional ophthalmically acceptable therapeutic agent.  
     
     
         8 . The implant of  claim 1 , wherein the alpha-2 adrenergic receptor agonist is dispersed within the biodegradable polymer matrix.  
     
     
         9 . The implant of  claim 1 , wherein the matrix comprises a mixture of a first biodegradable polymer of polylactic acid, and a different second biodegradable polymer of polylactic acid.  
     
     
         10 . The implant of  claim 9 , wherein the first biodegradable polymer has an inherent viscosity of about 0.3 dl/g.  
     
     
         11 . The implant of  claim 10 , wherein the second biodegradable polymer has an inherent viscosity of about 1.0 dl/g.  
     
     
         12 . The implant of  claim 1 , wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for more than one month from the time the implant is placed in the vitreous of the eye.  
     
     
         13 . The implant of  claim 1 , wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for more than forty days from the time the implant is placed in the vitreous of the eye.  
     
     
         14 . The implant of  claim 1 , wherein the matrix releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for less than 35 days from the time the implant is placed in the vitreous of the eye.  
     
     
         15 . The implant of  claim 1 , wherein the alpha-2 adrenergic receptor agonist is brimonidine, and the matrix releases drug at a rate effective to sustain release of a therapeutically effective amount of brimonidine for about three months.  
     
     
         16 . The implant of  claim 1 , wherein the implant is structured to be placed in the vitreous of the eye.  
     
     
         17 . The implant of  claim 1 , wherein the alpha-2 adrenergic receptor agonist is a brimonidine tartrate provided in an amount of about 20% by weight of the implant, and the biodegradable polymer matrix comprises a combination of two different polylactide polymers.  
     
     
         18 . The implant of  claim 1 , wherein the matrix comprises a mixture of biodegradable polymers, at least one of the biodegradable polymers is a polylactide having a molecular weight of about 64 kD.  
     
     
         19 . The implant of  claim 18 , wherein the mixture comprises a second polymer of a polylactide having a molecular weight of about 14 kD.  
     
     
         20 . The implant of  claim 1  which is formed by an extrusion process.  
     
     
         21 . A method of making a biodegradable intraocular implant, comprising the step of: extruding a mixture of an alpha-2 adrenergic receptor agonist and a biodegradable polymer component to form a biodegradable material that releases drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist from the implant for a time effective to reduce ocular vascular occlusion in an eye in which the implant is placed, the time being at least about one week after the implant is placed in the eye.  
     
     
         22 . The method of  claim 21 , wherein the alpha-2 adrenergic agonist is selected from the group consisting of quinoxalines, (2-imidozolin-2-ylamino)quinoxalines, 5-bromo-6-(2-imidozolin-2-ylamino)quinoxalines, derivatives thereof and mixtures thereof.  
     
     
         23 . The method of  claim 21 , wherein the alpha-2 adrenergic agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.  
     
     
         24 . The method of  claim 21 , further comprising a step of mixing the alpha-2 adrenergic receptor agonist with the polymer component before the extrusion step.  
     
     
         25 . The method of  claim 21 , wherein the alpha-2 adrenergic receptor agonist and the polymer component are in a powder form.  
     
     
         26 . The method of  claim 21 , wherein the polymer component comprises a mixture of biodegradable polymers, at least one of the biodegradable polymers is a polylactide having a molecular weight of about 64 kD.  
     
     
         27 . The method of  claim 21 , wherein the polymer component comprises a mixture of two different biodegradable polymers, one biodegradable polymer having an inherent viscosity of about 0.3 dl/g and the other biodegradable polymer having an inherent viscosity of about 1.0 dl/g.  
     
     
         28 . A method of reducing ocular occlusion in an eye of a patient, comprising the step of placing the implant of  claim 1  in an eye of the patient to provide a therapeutically effective amount of the alpha-2 adrenergic receptor agonist to the patient for at least about one week.  
     
     
         29 . The method of  claim 28 , wherein the method is effective to prevent an ocular condition selected from the group consisting of: retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, hemi-retinal vein occlusion, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (cad), eales disease and vasculopathies associated with diabetes.  
     
     
         30 . The method of  claim 28 , wherein the implant is placed in the posterior of the eye.  
     
     
         31 . The method of  claim 28 , wherein the implant is placed in the eye with a trocar.  
     
     
         32 . The method of  claim 28 , wherein the implant is placed in the eye with a syringe.  
     
     
         33 . The method of  claim 28 , further comprising a step of administering a therapeutic agent in addition to the alpha-2 adrenergic receptor agonist to the patient.  
     
     
         34 . A method of treating glaucoma, the method comprising the step of placing a biodegradable intraocular implant comprising an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer in an eye, thereby treating glaucoma.  
     
     
         35 . The method of  claim 34 , wherein the alpha-2 adrenergic receptor agonist is associated with the biodegradable polymer matrix so that a therapeutically effective amount of the alpha-2 adrenergic receptor agonist is released for less than about 35 days after being placed in the vitreous of an eye.  
     
     
         36 . The method of  claim 34 , wherein the alpha-2 adrenergic receptor agonist is associated with the biodegradable polymer matrix so that a therapeutically effective amount of the alpha-2 adrenergic receptor agonist is released for at least about 40 days after being placed in the vitreous of an eye.  
     
     
         37 . The method of  claim 34 , wherein the alpha-2 adrenergic receptor agonist is selected from the group consisting of brimonidine, salts thereof, and mixtures thereof.  
     
     
         38 . A method for improving or maintaining vision in a patient in need thereof, comprising the step of placing a biodegradable intraocular implant comprising an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer in an eye, thereby improving or maintaining vision of the patient.  
     
     
         39 . The method of  claim 38 , wherein the alpha-2 adrenergic receptor agonist is brimonidine, salts thereof, and mixtures thereof.  
     
     
         40 . The method of  claim 38 , wherein the placement of the implant in the eye is effective to treat at least one condition selected from the group consisting of Non-Exudative Age Related Macular Degeneration, Exudative Age Related Macular Degeneration, Choroidal Neovascularization, Diabetic Retinopathy, Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, Acute Multifocal Placoid Pigment Epitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy, Syphilis, Lyme, Tuberculosis, Toxoplasmosis, Intermediate Uveitis, Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome, Ocular Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome, Coat's Disease, Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid Streaks, Familial Exudative Vitreoretinopathy, Sympathetic Ophthalmia, Uveitic Retinal Disease, Retinal Detachment, Trauma, Laser, photodynamic therapy, Photocoagulation, Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow Transplant Retinopathy, Proliferative Vitreal Retinopathy and Epiretinal Membranes, Proliferative Diabetic Retinopathy, Ocular Histoplasmosis, Ocular Toxocariasis, Presumed Ocular Histoplasmosis Syndrome, Endophthalmitis, Toxoplasmosis, Retinal Diseases Associated with HIV Infection, Choroidal Disease Associated with HIV Infection, Uveitic Disease Associated with HIV Infection, Viral Retinitis, Acute Retinal Necrosis, Progressive Outer Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis, Retinitis Pigmentosa, Systemic Disorders with Accosiated Retinal Dystrophies, Congenital Stationary Night Blindness, Cone Dystrophies, Stargardt's Disease and Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy, pseudoxanthoma elasticum, Retinal Detachment, Macular Hole, Giant Retinal Tear, Retinal Disease Associated with Tumors, Congenital Hypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors, Punctate Inner Choroidopathy, Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal Degeneration, and Acute Retinal Pigment Epithelitis.  
     
     
         41 . A biodegradable intraocular implant comprising: 
 an alpha-2 adrenergic receptor agonist and a biodegradable polymer matrix that releases drug at a rate effective to sustain release of the alpha-2 adrenergic receptor agonist from the implant for at least about one week after the implant is placed in the eye.    
     
     
         42 . The implant of  claim 42 , wherein the alpha-2 adrenergic receptor agonist is brimonidine, salts thereof, and mixtures thereof.