Controlled Release Microparticles

Abstract

Formulations for controlled, sustained release of biologically active agents for the treatment of ocular disorders have been developed. These formulations are based on solid microparticles formed of the combination of biodegradable, synthetic polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof. The microparticles are characterized by low burst levels and efficient drug loading and sustained release.

We claim: 
     
         1 - 37 . (canceled) 
     
     
         38 . A method of treating an ocular disease of a patient in need thereof, comprising;
 a. providing a formulation comprising a plurality of microparticles comprising: (a) a core load of an anti-VEGF aptamer; and (b) poly(lactic acid) (PLA) or poly(lactic acid-co-glycolic acid) (PLGA) polymer;   b. suspending said formulation in a pharmaceutically acceptable liquid carrier to form a sustained release suspension composition for intravitreal administration;   c. injecting said suspension composition into the vitreous of the eye of the patient to treat the ocular disease, wherein said composition releases said aptamer over a period of at least 1 month with a 24 hour initial burst of less than 15 wt % of said core load from said microparticles.   
     
     
         39 . The method according to  claim 38 , wherein the ocular disease is chosen from optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, corneal neovascularization, vitreal neovascularization, glaucoma, pannus, pterygium, macular edema, vascular retinopathy, retinal degeneration, uveitis, inflammatory diseases of the retina, and proliferative vitreoretinopathy. 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . The method according to  claim 38 , wherein the ocular disease is macular degeneration. 
     
     
         43 . The method according to  claim 38 , wherein the anti-VEGF aptamer comprises pegaptanib. 
     
     
         44 . The method according to  claim 43 , wherein pegaptanib is released from the microparticles at a rate ranging from about 0.01 to about 10 micrograms (μg) per day. 
     
     
         45 . The method according to  claim 43 , wherein pegaptanib is released from the microparticles at a rate ranging from about 0.1 to about 6 μg per day. 
     
     
         46 . The method according to  claim 43 , wherein pegaptanib is released at a rate sufficient to achieve pegaptanib plasma concentrations of about 0.05-0.40 nM throughout an administration period of at least 3 weeks. 
     
     
         47 . The method according to  claim 43 , wherein pegaptanib is released at a rate sufficient to achieve pegaptanib plasma concentrations of about 0.05-0.40 nM throughout an administration period of at least 6 weeks. 
     
     
         48 . The method according to  claim 43 , wherein pegaptanib is released at a rate sufficient to achieve pegaptanib vitreous concentrations of about 10-30 ng/mL. 
     
     
         49 . The method of  claim 38 , wherein the microparticles release the anti-VEGF aptamer over a period of at least 3 months. 
     
     
         50 . The method of  claim 38 , wherein the microparticles release the anti-VEGF aptamer over a period of about 3-6 months. 
     
     
         51 . The method of  claim 38 , wherein the microparticles are syringable through a 29-gauge needle or narrower. 
     
     
         52 . The method of  claim 38 , wherein the microparticles have a mean diameter of about 30 μm. 
     
     
         53 . The method of  claim 38 , wherein the microparticles have a mean diameter of about 15 μm. 
     
     
         54 . The method of  claim 38 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 75% of the inner diameter of the needle. 
     
     
         55 . The method of  claim 38 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 50% of the inner diameter of the needle. 
     
     
         56 . The method of  claim 38 , wherein the microparticles are syringable through a 27-gauge needle or narrower and have a diameter of less than or equal to 25% of the inner diameter of the needle. 
     
     
         57 . The method of  claim 38 , wherein the microparticles have a core load of at least 10% by weight. 
     
     
         58 . The method of  claim 38 , wherein the microparticles have a core load of at least 15% by weight. 
     
     
         59 . The method of  claim 38 , wherein the microparticles have a core load of at least 20% by weight. 
     
     
         60 . The method of  claim 38 , wherein the microparticles exhibit a 24 hour burst of less than 10 wt % of said core load. 
     
     
         61 . The method of  claim 38 , wherein the microparticles exhibit a 24 hour burst of less than 5 wt % of said core load. 
     
     
         62 . The method of  claim 38 , wherein the polymer has a smooth, non-pitted external morphology. 
     
     
         63 . The method of  claim 62 , wherein the polymer has a monomer ratio of lactid:glycolide in the range of about 40:60 to 100:0. 
     
     
         64 . The method of  claim 38 , wherein the suspension comprises 100-300 mg microparticles per mL of the liquid carrier. 
     
     
         65 . The method of  claim 38 , wherein the microparticles have a particle size distribution in the range of 10 μm to 45 μm in diameter. 
     
     
         66 . The method of  claim 38 , wherein the core load of the anti-VEGF aptamer is at least 7 wt %. 
     
     
         67 . The method of  claim 38 , wherein the liquid carrier comprises a surfactant. 
     
     
         68 . The method of  claim 67 , wherein the surfactant is chosen from poly(vinyl alcohol), carboxymethyl cellulose, lecithin, gelatin, poly(vinyl pyrrolidone), polyoxyethylenesorbitan fatty acid esters, sodium dodecyl sulfate and mannitol. 
     
     
         69 . The method of  claim 68 , wherein the surfactant is chosen from polyoxyethylenesorbitan fatty acid esters, sodium dodecyl sulfate and mannitol.