Linear cyclodextrin copolymers

Abstract

Linear cyclodextrin copolymers and linear oxidized cyclodextrin copolymers containing an unoxidized and/or an oxidized cyclodextrin moiety integrated into the polymer backbone are described. Methods of preparing such copolymers are also described. The linear cyclodextrin copolymer and linear oxidized cyclodextrin copolymer of the invention may be used as a delivery vehicle of various therapeutic agents.

1 - 45 . (canceled)  
     
     
         46 . A water-soluble, linear cyclodextrin copolymer having a linear polymer backbone, the copolymer including a plurality of cyclodextrin monomer moieties and linker moieties in the polymer backbone, wherein, unless the cyclodextrin monomer moiety or the linker moiety is present at the terminus of a polymer chain, each of the cyclodextrin monomer moieties is attached to two of the linker moieties, and each of the linker moieties covalently links two cyclodextrin monomer moieties, and wherein the cyclodextrin monomer moieties are unsubstituted or substituted by groups that do not interfere with the copolymerization with the linker moiety.  
     
     
         47 . The copolymer of  claim 46 , wherein the cyclodextrin monomer moieties are the same or different throughout the polymer.  
     
     
         48 . The polymer of  claim 46 , comprising repeating units of Formula Ia, Ib, or a combination thereof:  
       
         
           
           
               
               
           
         
         wherein C is a substituted or unsubstituted cyclodextrin monomer moiety, and A is a linker moiety bound to the cyclodextrin monomer moiety C.  
       
     
     
         49 . The copolymer of  claim 46 , wherein the cyclodextrin monomer moieties are substituted or unsubstituted α-, β-, or γ-cyclodextrin, or a combination thereof.  
     
     
         50 . The copolymer of  claim 46 , wherein the cyclodextrin monomer moieties are independently selected from 6 A ,6 B -deoxy-α-cyclodextrin, 6 A ,6 C -deoxy-α-cyclodextrin, 6 A ,6 D -deoxy-α-cyclodextrin, 6 A ,6 B -deoxy-β-cyclodextrin, 6 A ,6 C -deoxy-β-cyclodextrin, 6 A ,6 D -deoxy-β-cyclodextrin, 6 A ,6 B -deoxy-γ-cyclodextrin, 6 A ,6 C -deoxy-γ-cyclodextrin, 6 A ,6 D -deoxy-γ-cyclodextrin, and 6 A ,6 E -deoxy-γ-cyclodextrin.  
     
     
         51 . The copolymer of  claim 46 , wherein the cyclodextrin monomer moiety has the general Formula III:  
       
         
           
           
               
               
           
         
         wherein p=5-7.  
       
     
     
         52 . The cyclodextrin copolymer of  claim 46 , wherein the cyclodextrin monomer moieties are, independently, selected from 2 A ,3 A -deoxy-2 A ,3 A -dihydro-α-cyclodextrin, 2 A ,3 A -deoxy-2 A ,3 A -dihydro-β-cyclodextrin, and 2 A ,3 A -deoxy-2 A ,3 A -dihydro-γ-cyclodextrin.  
     
     
         53 . The cyclodextrin copolymer of  claim 46 , wherein the linker moiety is biodegradable or acid-labile.  
     
     
         54 . The cyclodextrin copolymer of  claim 46 , wherein the cyclodextrin copolymer is crosslinked to a polymer.  
     
     
         55 . The cyclodextrin copolymer of  claim 46 , wherein at least one ligand is bound to the linear cyclodextrin copolymer.  
     
     
         56 . A composition comprising: 
 a cyclodextrin copolymer as defined in  claim 46;  and    a therapeutic agent.    
     
     
         57 . A method for preparing a water-soluble, linear cyclodextrin copolymer comprising: 
 (a) providing at least one cyclodextrin comonomer precursor which is disubstituted with a leaving group.    (b) reacting the cyclodextrin monomer precursor with a linker precursor comprising at least two functional groups through which a linkage of the cyclodextrin monomer precursor can be achieved,    whereby a water-soluble, linear cyclodextrin copolymer comprising alternating units of cyclodextrin monomer moieties and linker moieties is prepared.    
     
     
         58 . The method of  claim 57 , wherein at least one cyclodextrin monomer moiety of the cyclodextrin copolymer has been modified with at least one ligand.  
     
     
         59 . The method of  claim 58 , wherein the ligand is selected from vitamins, proteins, and polysaccharides.  
     
     
         60 . The method of  claim 57 , comprising: 
 polymerizing a cyclodextrin monomer precursor, where the cyclodextrin monomer precursor is disubstituted with the same or different leaving group, with a linker A precursor capable of displacing the leaving groups to form the water-soluble linear cyclodextrin copolymer having repeating units of Formula Ia, Ib, or a combination thereof:                          wherein C is a substituted or unsubstituted cyclodextrin monomer moiety, and A is a linker moiety bound to the cyclodextrin derivative C.    
     
     
         61 . The method of any one of claims  57  or  60 , wherein the cyclodextrin monomer precursor is a diiodinated cyclodextrin monomer precursor of Formula IVa, IVb, IVc, or a mixture thereof:  
       
         
           
           
               
               
           
         
       
     
     
         62 . The method of  claim 61 , further comprising reacting the linear cyclodextrin copolymer with a ligand to form a linear cyclodextrin copolymer having at least one ligand bound to the copolymer.  
     
     
         63 . The method of any one of claims  57  or  60 , wherein the cyclodextrin monomer moieties are derived from α-, β-, γ-cyclodextrin, or a combination thereof.  
     
     
         64 . The method of  claim 61 , further comprising: 
 (a) aminating the diiodinated cyclodextrin monomer precursor to form a diaminated cyclodextrin monomer precursor; and    (b) copolymerizing the diaminated cyclodextrin monomer precursor to form the water-soluble, linear cyclodextrin copolymer.    
     
     
         65 . A method of producing a crosslinked cyclodextrin copolymer, comprising: 
 reacting at least one linear cyclodextrin copolymer having a repeating unit of Formula Ia, Ib, or a combination thereof:                          wherein C is a substituted or unsubstituted cyclodextrin monomer moiety, and A is a linker moiety bound to the cyclodextrin monomer moiety C,    with a polymer in the presence of a crosslinking agent.    
     
     
         66 . The method of  claim 65 , wherein the polymer is a linear cyclodextrin copolymer or a linear oxidized cyclodextrin copolymer.  
     
     
         67 . A copolymer prepared by the method of  claim 57 .  
     
     
         68 . A composition comprising the copolymer of any one of claims  46  or  67  and an agriculturally biologically active compound.  
     
     
         69 . The composition of  claim 68 , wherein the agriculturally biologically active compound is selected from a fungicide, herbicide, insecticide, and mildeweide.