Alpha-2 agonist polymeric drug delivery systems

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 can be placed in an eye to treat one or more ocular conditions, such as an ocular vasculopathy or glaucoma, including reduction of an elevated intraocular pressure.

We claim: 
     
         1 . A biodegradable intraocular implant comprising brimonidine free base in an amount in the range of 1 wt % to 50 wt %, and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer. 
     
     
         2 . The implant of  claim 1 , wherein the implant comprises from about 10% to about 91% ester end-capped biodegradable polymer, from about 5 wt % to about 40 wt % acid end-capped biodegradable polymer, and from about 4 wt % to about 50 wt % brimonidine free base. 
     
     
         3 . The implant of  claim 2 , wherein the implant comprises from about 25% to about 80% ester end-capped biodegradable polymer, from about 10 wt % to about 40 wt % acid end-capped biodegradable polymer, and about 10 wt % to about 35 wt % brimonidine free base. 
     
     
         4 . The implant of  claim 2 , wherein the implant comprises about 88 wt % ester end-capped biodegradable polymer, about 10 wt % acid end-capped biodegradable polymer, and about 12 wt % brimonidine free base. 
     
     
         5 . The implant of  claim 2 , wherein the implant comprises from about 53 wt % to about 73% ester end-capped biodegradable polymer, from about 15 wt % to about 35 wt % acid end-capped biodegradable polymer, and from about 9 wt % to about 12 wt % brimonidine free base. 
     
     
         6 . The implant of  claim 2 , wherein the biodegradable polymer comprises more than one ester end-capped biodegradable polymer. 
     
     
         7 . The implant of  claim 2 , wherein the biodegradable polymer comprises more than one acid end-capped biodegradable polymer. 
     
     
         8 . The implant of  claim 2 , wherein the implant has no or a nominal lag time after ocular implantation or insertion of the implant before release of a therapeutically effective amount of the brimonidine free base from the implant occurs. 
     
     
         9 . The implant of  claim 1  which does not include any pore forming additives, release rate modulators or release rate modifiers. 
     
     
         10 . The implant of  claim 1 , wherein the implant can exhibit a sustained release of the brimonidine free base from the biodegradable polymeric matrix over a period of at least 115 days. 
     
     
         11 . The implant of  claim 1 , wherein the implant exhibits a substantially linear release of the brimonidine free base from the biodegradable polymeric matrix of the implant over a period of time of from about 20 days to about 50 days. 
     
     
         12 . A process for making a biodegradable intraocular implant comprising:
 (a) mixing a brimonidine free base and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer;   (b) heating the mixture, and;   (c) extruding the heated mixture, to thereby make a biodegradable intraocular implant.   
     
     
         13 . A biodegradable intraocular implant made by the process of  claim 12 , wherein the brimonidine free base is homogenously distributed throughout the implant. 
     
     
         14 . A method for treating an ocular condition selected from the group consisting of: macular degeneration, age related macular degeneration, non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, retinopathy, diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, and diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, syphilis, lyme disease, tuberculosis, toxoplasmosis, uveitis, intermediate uveitis, pars planitis, and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome, ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease, frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, eye trauma, laser induced eye damage, photocoagulation, eye hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy, proliferative vitreal retinopathy, appearance of 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 associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Bests 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, acute retinal pigment epithelitis, the method comprising the step of intraocular administration of a biodegradable intraocular implant comprising brimonidine free base and a biodegradable polymer, wherein the biodegradable polymer comprises an ester end-capped biodegradable polymer and an acid end-capped biodegradable polymer.