Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents

Abstract

Combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant are shown to modulate each other's rate of release. Formulations of a therapeutically active agent and modulator provide substantially constant rate of release for an extended period of time.

1 - 9 . (canceled)  
     
     
         10 . A sustained release device including a corticosteroid disposed therein, which device is dimensioned for implantation in the vitreal chamber or the posterior segment of a patient's eye and configured to have a release rate for said corticosteroid of at least about 1 μg per day over a time course of at least 4 weeks after implantation, which release rate results in an aqueous humor corticosteroid concentration less than one tenth the vitreous corticosteroid concentration.  
     
     
         11 . The sustained release device of  claim 10 , wherein the release rate results in an aqueous humor corticosteroid concentration of less than 0.05 μg/ml over said time course.  
     
     
         12 . The device of  claim 10 , wherein said corticosteroid is selected from dexamethasone, hydrocortisone, cortisone, prednisone, prednisone, progesterone-like compounds, medrysone and fluorometholone.  
     
     
         13 . The device of  claim 10 , wherein the corticosteroid is released with about zero order kinetics.  
     
     
         14 . The device of  claim 10 , which release rate results in an aqueous humor corticosteroid concentration which does not cause an adverse effect in the anterior chamber of the eye over said time course.  
     
     
         15 . A sustained release device including a corticosteroid disposed therein, which device is dimensioned for implantation in the vitreal chamber or the posterior segment of a patient's eye and configured to have a release rate for said corticosteroid to produce a sustained and therapeutic concentration of said corticosteroid over a time course of at least 4 weeks effective for reducing diabetic retinopathy, which release rate results in an insignificant or undetectable aqueous humor corticosteroid concentration over said time course.  
     
     
         16 . The device of  claim 15 , wherein said corticosteroid is selected from dexamethasone, hydrocortisone, cortisone, prednisone, prednisone, progesterone-like compounds, medrysone and fluorometholone.  
     
     
         17 . The device of  claim 16 , wherein the aqueous humor corticosteroid concentration is 0 to <0.02 μg/ml.  
     
     
         18 . The device of  claim 16 , wherein the corticosteroid is released with about zero order kinetics.  
     
     
         19 . A sustained release device including a steroid disposed therein, which device is dimensioned for implantation in the vitreal chamber or the posterior segment of a patient's eye and configured to release a therapeutically effective amount of steroid, which amount does not produce toxicity.  
     
     
         20 . The device of  claim 19 , wherein the steroid is released with about zero order kinetics.  
     
     
         21 . A method for treating or preventing ocular diseases, comprising administering a corticosteroid to a posterior segment of an eye to provide sustained release of a therapeutic concentration of said corticosteroid in the vitreous of the eye while not exceeding a non-toxic concentration of corticosteroid in the aqueous of the eye.  
     
     
         22 . A method according to  claim 21 , wherein the aqueous humor corticosteroid concentration is 0 to <0.02 μg/ml.  
     
     
         23 . A method according to  claim 21 , wherein said therapeutic concentration of corticosteroid persists for more than 1 month.  
     
     
         24 . A method according to  claim 21 , wherein said therapeutic concentration of corticosteroid persists for more than 6 months.  
     
     
         25 . A method according to  claim 21 , wherein a disease state to be treated is selected from the group consisting of ocular inflammation and retinal degeneration.  
     
     
         26 . A method according to  claim 21 , wherein corticosteroid is released with about zero order kinetics.  
     
     
         27 . A method according to  claim 21 , wherein corticosteroid is released at a mean release rate of at least about 1 μg/day.  
     
     
         28 . A method according to  claim 21 , wherein corticosteroid is released at a mean release rate of at least about 1 μg/day over a time course of at least 4 weeks, which release rate results in an aqueous humor corticosteroid concentration of less than one tenth the vitreous corticosteroid concentration.  
     
     
         29 . A method according to  claim 21 , wherein the release rate for corticosteroid produces a sustained and therapeutic concentration of corticosteroid over a time course of at least 4 weeks effective for reducing neovascularization, edema, or diabetic retinopathy, which release rate results in an aqueous humor corticosteroid concentration which does not cause an adverse increase in intraocular pressure over said time course.  
     
     
         30 . A method according to  claim 28 , wherein the release rate for said corticosteroid is at least about 1 μg/day over a time course of at least 4 weeks, and which release rate also results in an aqueous humor concentration of corticosteroid of less than 0.02 μg/ml over said time course.  
     
     
         31 . A method according to  claim 21 , which does not produce toxicity.  
     
     
         32 . A method for treating or preventing ocular diseases, comprising administering corticosteroid to a posterior segment of an eye to produce a sustained therapeutic concentration of corticosteroid for a period of at least 1 month, wherein the aqueous concentration of corticosteroid is less than the vitreous concentration of corticosteroid during said period.  
     
     
         33 . A method according to  claim 32 , wherein the aqueous concentration of corticosteroid is non-toxic and is less than 0.02 μg/ml.  
     
     
         34 . A method according to  claim 32 , wherein said therapeutic concentration of corticosteroid persists for more than 1 month.  
     
     
         35 . A method according to  claim 32 , wherein said therapeutic concentration of corticosteroid persists for more than 6 months.  
     
     
         36 . A method according to  claim 32 , wherein a disease state to be treated is selected from the group consisting of ocular inflammation and retinal degeneration.  
     
     
         37 . A method according to  claim 32 , wherein corticosteroid is released at a mean release rate of at least about 1 μg/day.  
     
     
         38 . A method according to  claim 32 , wherein the release rate for corticosteroid produces a sustained and therapeutic concentration of corticosteroid over a time course of at least 4 weeks effective for reducing neovascularization, edema, or diabetic retinopathy, which release rate results in an aqueous humor fluocinolone acetonide concentration which does not cause an adverse increase in intraocular pressure over said time course.