Non-linear multiblock copolymer-drug conjugates for the delivery of active agents

Abstract

Non-linear multiblock copolymer-drug conjugates for the treatment and prevention of diseases and disorders of the eye are provided. The polymer-drug conjugates can form nanoparticles, microparticles, and implants that are capable of effectively delivering therapeutic levels of one or more active agents for an extended period of time. Administration to the eye of an active agent in the form of a non-linear multiblock copolymer-drug conjugate produces decreased side effects when compared to administration of the active agent alone. Also provided are methods of treating intraocular neovascular diseases, such as wet age-related macular degeneration as well as diseases and disorders of the eye associated with inflammation, such as uveitis.

1 .- 18 . (canceled) 
     
     
         19 . A polymer conjugate of the formula 
       
         
           
           
               
               
           
         
         wherein 
         A is an ophthalmic drug for treatment of the posterior segment of the eye, wherein A is an anti-angiogenesis agent; 
         Z is a hydrophilic polymer segment wherein the segment is poly(ethylene glycol); 
         Y is a multivalent branch point that is an organic, inorganic, or organometallic moiety; 
         X is a hydrophobic polymer segment wherein the segment is selected from a poly(lactic acid) segment, a poly(glycolic acid) segment, and a poly(lactic-co-glycolic acid) segment; and 
         m and n are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
       
     
     
         20 . The polymer conjugate of  claim 19 , wherein Y is selected from 
       
         
           
           
               
               
           
         
       
     
     
         21 . The polymer conjugate of  claim 19 , wherein X is a poly(lactic acid) segment. 
     
     
         22 . The polymer conjugate of  claim 19 , wherein A is an anti-vascular endothelial growth factor (VEGF) compound, a receptor tyrosine kinase inhibitor, or a tyrosine kinase inhibitor. 
     
     
         23 . The polymer conjugate of  claim 19 , wherein A is an anti-VEGF compound. 
     
     
         24 . The polymer conjugate of  claim 19 , wherein A is a receptor tyrosine kinase inhibitor. 
     
     
         25 . The polymer conjugate of  claim 19 , wherein A is a tyrosine kinase inhibitor. 
     
     
         26 . The polymer conjugate of  claim 19 , wherein X is a poly(glycolic acid) segment. 
     
     
         27 . The polymer conjugate of  claim 26 , wherein A is an anti-VEGF compound. 
     
     
         28 . The polymer conjugate of  claim 26 , wherein A is a receptor tyrosine kinase inhibitor. 
     
     
         29 . The polymer conjugate of  claim 26 , wherein A is a tyrosine kinase inhibitor. 
     
     
         30 . The polymer conjugate of  claim 19 , wherein X is a poly(lactic-co-glycolic acid) segment. 
     
     
         31 . The polymer conjugate of  claim 30 , wherein A is an anti-VEGF compound. 
     
     
         32 . The polymer conjugate of  claim 30 , wherein A is a receptor tyrosine kinase inhibitor. 
     
     
         33 . The polymer conjugate of  claim 30 , wherein A is a tyrosine kinase inhibitor. 
     
     
         34 . A pharmaceutical composition containing microparticles comprising the polymer conjugate of  claim 19  and a pharmaceutically acceptable excipient. 
     
     
         35 . A method of treating a disease or disorder of the posterior segment of the eye selected from wet-age related macular degeneration, choroidal neovascularization, glaucoma, proliferative retinopathies, and retinal neovascularization comprising administering to a patient in need thereof the pharmaceutical composition of  claim 34 . 
     
     
         36 . The method of  claim 35 , wherein the pharmaceutical composition is administered via intravitreal injection, subconjunctival injection, intracameral injection, intrastromal injection, subretinal injection, or intraocular injection.