Microsphere Drug Delivery System for Sustained Intraocular Release

Abstract

Disclosed are biodegradable microspheres between 40 μm and 200 μm in diameter that are effectively retained in the anterior chamber of the eye without producing hyperemia. The microspheres generally contain a drug effective for the treatment of an ocular condition and include a biodegradable polymer matrix that can provide for the sustained (>7 day) release of the drug following administration to the anterior chamber of the eye. Methods for making and using the microspheres to treat an ocular condition are also disclosed.

What is claimed is: 
     
         1 . A drug delivery system effective for the treatment of an ocular condition,
 the system comprising a plurality of biodegradable microspheres and an ophthalmically acceptable carrier;   the biodegradable microspheres having diameters no less than 40 microns and no greater than 200 microns and comprising a biodegradable polymer matrix and a therapeutic agent effective for the treatment of the ocular condition;   such that the drug delivery system comprises no microspheres smaller than 40 microns and no microspheres larger than 200 microns; and   wherein the drug delivery system releases a therapeutically effective amount of the therapeutic agent for at least one week after the system is placed in the eye of a mammal.   
     
     
         2 . The drug delivery system according to  claim 1 , wherein the microspheres present in the drug delivery system are produced by an emulsion process. 
     
     
         3 . The drug delivery system according to  claim 2 , wherein the plurality of biodegradable microspheres present in the drug delivery system have diameters no less than about 106 μm and no greater than about 180 μm, such that the drug delivery system comprises no microspheres smaller than about 106 μm and no microspheres larger than about 180 μm. 
     
     
         4 . The drug delivery system according to  claim 3 , wherein the mean diameter of the microspheres present in the drug delivery system is between 100 μm and 150 μm. 
     
     
         5 . The drug delivery system according to  claim 4 , wherein the mean diameter of the microspheres present in the drug delivery system is between 110 μm and 150 μm. 
     
     
         6 . The drug delivery system according to  claim 4 , wherein the ocular condition is glaucoma, elevated intraocular pressure, neovascularization, or inflammation. 
     
     
         7 . The drug delivery system according to  claim 6 , wherein the therapeutic agent is a prostamide, prostaglandin, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, alpha 2 adrenergic receptor agonist, or tyrosine kinase inhibitor. 
     
     
         8 . The drug delivery system according to  claim 7 , wherein the ocular condition is glaucoma or an inflammation of an eye of a patient and the therapeutic agent is bimatoprost, a steroidal anti-inflammatory agent, or a non-steroidal anti-inflammatory agent. 
     
     
         9 . The drug delivery system according to  claim 8 , wherein the ocular condition is glaucoma or elevated intraocular pressure and the therapeutic agent is bimatoprost and the drug delivery system comprises no therapeutic agent other than bimatoprost. 
     
     
         10 . The drug delivery system of  claim 7 , wherein the therapeutic agent is the compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         11 . The drug delivery system according to  claim 6 , wherein the ophthalmically acceptable carrier is an aqueous liquid or gel comprising a hyaluronic acid, a sodium hyaluronate, a hydroxyethyl cellulose (HEC), a carboxymethylcellulose (CMC), a hydroxypropylmethyl cellulose (HPMC), a polyvinylproline (PVP), or a pluronic polymer. 
     
     
         12 . The drug delivery system according to  claim 11 , wherein the ophthalmically acceptable carrier is an aqueous gel comprising 2.5% w/v sodium hyaluronate. 
     
     
         13 . The drug delivery system according to  claim 11 , wherein the biodegradable polymer matrix comprises a poly(D,L-lactide), a poly(D,L-lactide-co-glycolide), or a mixture thereof. 
     
     
         14 . The drug delivery system according to  claim 13 , wherein the poly(D,L-lactide) and/or poly(D,L-lactide-co-glycolide) are independently selected from the group consisting of RESOMER® R203S, R203H, RG752H, RG755, RG502H, RG752S, R202H, R202S, and RG753S 
     
     
         15 . The drug delivery system according to  claim 14 , wherein the biodegradable polymer matrix further comprises a polyethylene glycol (PEG). 
     
     
         16 . The drug delivery system according to  claim 15 , wherein the PEG is PEG 3350, PEG 4400, or PEG 8000. 
     
     
         17 . The drug delivery system according to  claim 15 , wherein the therapeutic agent is bimatoprost and the ocular condition is glaucoma. 
     
     
         18 . An apparatus for injecting a drug delivery system into the eye of a mammal, said apparatus comprising a cannula, said cannula having a proximal end, a distal sharp end, and a lumen extending therethrough, the cannula further comprising a drug delivery system as defined by  claim 7 , wherein the drug delivery system is located within the lumen of the cannula. 
     
     
         19 . A method for treating an ocular condition in an eye of a patient, the method comprising placing a drug delivery system according to  claim 7  in the anterior chamber of the eye, thereby reducing at least one symptom of the ocular condition in the eye for at least one week. 
     
     
         20 . A method for making a population of biodegradable microspheres, the process comprising
 dissolving a biodegradable polymer or combination of two or more biodegradable polymers and a quantity of therapeutic agent in an organic solvent or mixture of solvents to form a solution;   adding a saturating or non-saturating quantity of therapeutic agent to an aqueous solution of polyvinyl alcohol to form a second solution;   adding the first solution to the second solution dropwise under constant stirring to form an emulsion;   evaporating the solvent(s) under constant stirring to form a suspension;   filtering the suspension through first and second sieves, wherein the mesh size of the first sieve is larger than the mesh size of the second sieve, thereby collecting particles with diameters less than the mesh size of the first sieve and greater than the mesh size of the second sieve;   centrifuging the collected particles to obtain a pellet; and   lyophilizing the pellet, thereby obtaining a microsphere population.   
     
     
         21 . The population of microspheres produced by the method of  claim 20 .