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.

The claimed invention is: 
     
         1 . A linear cyclodextrin copolymer comprising a repeating unit of formula Ia, Ib, or a combination thereof: 
       
         
           
           
               
               
           
         
       
       wherein C is a substituted or unsubstituted cyclodextrin monomer and A is a comonomer bound to cyclodextrin C. 
     
     
         2 . A cyclodextrin copolymer of  claim 1 , wherein said cyclodextrin monomer is an α-, β-, γ-cyclodextrin, or combination thereof. 
     
     
         3 . A cyclodextrin copolymer of  claim 1 , wherein said cyclodextrin monomer has the general formula (II): 
       
         
           
           
               
               
           
         
       
       and is selected from the group consisting of: 6 A ,6 B -deoxy-α-cyclodextrin (n=0, m=4), 6 A ,6 C -deoxy-α-cyclodextrin (n=1, m=3), 6 A ,6 D -deoxy-α-cyclodextrin (n=2, m=2), 6 A ,6 B -deoxy-β-cyclodextrin (n=0, m=5), 6 A ,6 C -deoxy-β-cyclodextrin (n=1, m=4), 6 A -6 C -deoxy-β-cyclodextrin (n=2, m=3), 6 A ,6 B -deoxy-γ-cyclodextrin (n=0, m=6), 6 A ,6 C -deoxy-γ-cyclodextrin (n=1, m=5), 6 A ,6 D -deoxy-γ-cyclodextrin (n=2, m=4), and 6 A ,6 E -deoxy-γ-cyclodextrin (n=3, m=3). 
     
     
         4 . A cyclodextrin copolymer of  claim 1 , wherein said cyclodextrin monomer has the general formula (III): 
       
         
           
           
               
               
           
         
       
       where p=5-7. 
     
     
         5 . A cyclodextrin copolymer of  claim 4 , wherein said cyclodextrin monomer is selected from the group consisting of 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. 
     
     
         6 . A cyclodextrin copolymer of  claim 1 , wherein A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       where x=1-50, and y+z=x. 
     
     
         7 . A cyclodextrin copolymer of  claim 1 , wherein A is biodegradable or acid-labile. 
     
     
         8 . A cyclodextrin copolymer of  claim 1 , wherein the cyclodextrin copolymer is crosslinked to a polymer. 
     
     
         9 . A cyclodextrin copolymer of  claim 8 , wherein at least one ligand is bound to the linear cyclodextrin copolymer. 
     
     
         10 . A cyclodextrin copolymer of  claim 1 , wherein at least one ligand is bound to the linear cyclodextrin copolymer. 
     
     
         11 . A cyclodextrin copolymer of  claim 1 , wherein at least one cyclodextrin monomer C is oxidized. 
     
     
         12 . A cyclodextrin copolymer of  claim 11 , wherein said cyclodextrin monomer is an α-, β-, γ-cyclodextrin, or combination thereof. 
     
     
         13 . A cyclodextrin copolymer of  claim 11 , wherein the cyclodextrin copolymer is crosslinked to a polymer. 
     
     
         14 . A cyclodextrin copolymer of  claim 13 , wherein at least one ligand is bound to the linear oxidized cyclodextrin copolymer. 
     
     
         15 . A cyclodextrin copolymer of  claim 11 , wherein at least one ligand is bound to the linear oxidized cyclodextrin copolymer. 
     
     
         16 . A cyclodextrin copolymer of  claim 1 , wherein substantially all of the cyclodextrin monomers are oxidized. 
     
     
         17 . A cyclodextrin copolymer of  claim 1 , wherein all of the cyclodextrin monomers are oxidized. 
     
     
         18 . A therapeutic composition comprising a cyclodextrin copolymer of  claim 1 ,  8 ,  9 ,  10 ,  11 ,  13 ,  14  or  15  and a therapeutic agent. 
     
     
         19 . A cyclodextrin composition comprising:
 a first linear cyclodextrin polymer comprising a repeating unit of formula Ia, Ib, or a combination thereof:   
       
         
           
           
               
               
           
         
       
       wherein C is a substituted or unsubstituted cyclodextrin monomer and A is a comonomer bound to cyclodextrin C; and
 a second linear cyclodextrin copolymer comprising a repeating unit of formula Ia, Ib, or a combination thereof wherein at least one cyclodextrin monomer C of said second linear cyclodextrin copolymer is oxidized. 
 
     
     
         20 . A composition of  claim 19 , wherein at least one of said first linear cyclodextrin copolymer and said second linear cyclodextrin copolymer is crosslinked to another polymer. 
     
     
         21 . A composition of  claim 20 , wherein at least one ligand is bound to at least one of said first linear cyclodextrin copolymer and said second linear cyclodextrin copolymer. 
     
     
         22 . A composition of  claim 19 , wherein at least one ligand is bound to at least one of said first linear cyclodextrin copolymer and said second linear cyclodextrin copolymer. 
     
     
         23 . A therapeutic composition comprising a cyclodextrin composition of  claim 19 ,  20 ,  21  or  22  and a therapeutic agent. 
     
     
         24 . A method of preparing a linear cyclodextrin copolymer comprising the steps of:
 copolymerizing a cyclodextrin monomer precursor, where said cyclodextrin monomer precursor is disubstituted with the same or different leaving group, with a comonomer A precursor capable of displacing said leaving groups to form a linear cyclodextrin copolymer having a repeating unit of formula Ia, Ib, or a combination thereof:   
       
         
           
           
               
               
           
         
       
       wherein C is a substituted or unsubstituted cyclodextrin monomer and A is a comonomer bound to cyclodextrin C. 
     
     
         25 . A method of preparing a linear cyclodextrin copolymer of  claim 24 , wherein said disubstituted cyclodextrin monomer precursor is a diiodinated cyclodextrin monomer precursor of formula IVa, IVb, IVc or a mixture thereof: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A method of  claim 24 , wherein said cyclodextrin monomer C is an α-, β-, γ-cyclodextrin or combination thereof. 
     
     
         27 . A method of  claim 24 , wherein said cyclodextrin monomer has the general formula (II): 
       
         
           
           
               
               
           
         
       
       and is selected from the group consisting of: 6 A ,6 B -deoxy-α-cyclodextrin (n=0, m=4), 6 A ,6 C -deoxy-α-cyclodextrin (n=1, m=3), 6 A ,6 D -deoxy-α-cyclodextrin (n=2, m=2), 6 A ,6 B -deoxy-β-cyclodextrin (n=0, m=5), 6 A ,6 C -deoxy-β-cyclodextrin (n=1, m=4), 6 A -6 D -deoxy-β-cyclodextrin (n=2, m=3), 6 A ,6 B -deoxy-γ-cyclodextrin (n=0, m=6), 6 A ,6 C -deoxy-γ-cyclodextrin (n=1, m=5), 6 A ,6 D -deoxy-γ-cyclodextrin (n=2, m=4), and 6 A ,6 E -deoxy-γ-cyclodextrin (n=3, m=3). 
     
     
         28 . A method of  claim 24 , wherein said cyclodextrin monomer has the general formula (III): 
       
         
           
           
               
               
           
         
       
       where p=5-7. 
     
     
         29 . A method of  claim 28 , wherein said cyclodextrin monomer is selected from the group consisting of 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. 
     
     
         30 . A method of  claim 24 , wherein A is selected from the group consisting of:— 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       where x=1-50, and y+z=x. 
     
     
         31 . A method of  claim 24  further comprising the step of reacting said linear cyclodextrin copolymer with a ligand to form a linear cyclodextrin copolymer having at least one ligand bound to the copolymer 
     
     
         32 . A method of  claim 25 , further comprising the step of
 aminating said diiodinated cyclodextrin monomer precursor to form a diaminated cyclodextrin monomer precursor; and   copolymerizing said diaminated cyclodextrin monomer precursor to form said cyclodextrin copolymer having a repeating unit of formula Ia, Ib, or a combination thereof.   
     
     
         33 . A method of  claim 32 , wherein said diaminated cyclodextrin monomer precursor is of formula Va, Vb, Vc or a mixture thereof: 
       
         
           
           
               
               
           
         
       
     
     
         34 . A method of  claim 32 , wherein said diaminated cyclodextrin monomer precursor is of formula Vd, Ve, Vf or a mixture thereof: 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method of preparing a linear cyclodextrin copolymer comprising the step of reducing a linear oxidized cyclodextrin copolymer, with the proviso that said linear oxidized cyclodextrin copolymer does not contain a reducible comonomer A. 
     
     
         36 . A method of preparing a linear oxidized cyclodextrin copolymer comprising the step of:
 oxidizing a cyclodextrin copolymer having a repeating unit of formula Ia, Ib, or a combination thereof:   
       
         
           
           
               
               
           
         
       
       wherein C is a substituted or unsubstituted oxidized cyclodextrin monomer and A is a comonomer bound to cyclodextrin monomer C. 
     
     
         37 . A method of  claim 34  further comprising the step of reacting said linear oxidized cyclodextrin copolymer with a ligand to form a linear oxidized cyclodextrin copolymer having at least one ligand bound to the copolymer. 
     
     
         38 . A method of preparing a linear oxidized cyclodextrin copolymer comprising the steps of:
 (a) iodinating an oxidized cyclodextrin monomer precursor to form an oxidized diiodinated cyclodextrin monomer precursor of formula VIIa, VIIb, VIIc or a mixture thereof:   
       
         
           
           
               
               
           
         
       
       and
 (b) copolymerizing said oxidized diiodinated cyclodextrin monomer precursor with a comonomer A precursor to form a linear oxidized cyclodextrin copolymer having a repeating unit of formula VIa, VIb, or a combination thereof 
 
       
         
           
           
               
               
           
         
       
       wherein C is a substituted or unsubstituted oxidized cyclodextrin monomer and A is a comonomer bound to the cyclodextrin monomer C. 
     
     
         39 . A method of  claim 38  further comprising the step of reacting said linear oxidized cyclodextrin copolymer with a ligand to form a linear oxidized cyclodextrin copolymer having at least one ligand bound to the copolymer. 
     
     
         40 . A method of  claim 38  further comprising the steps of aminating said oxidized diiodinated cyclodextrin monomer precursor to form an oxidized diaminated cyclodextrin monomer precursor of formula VIIIa, VIIIb, VIIIc or a mixture thereof: 
       
         
           
           
               
               
           
         
         copolymerizing said oxidized diaminated cyclodextrin monomer precursor with a comonomer A precursor to form said linear oxidized cyclodextrin copolymer having a repeating unit of formula VIa, VIb, or a combination thereof. 
       
     
     
         41 . A method of  claim 38  further comprising the steps of aminating said oxidized diiodinated cyclodextrin monomer precursor to form an oxidized diaminated cyclodextrin monomer precursor of formula IXa, IXb, IXc or a mixture thereof: 
       
         
           
           
               
               
           
         
       
     
     
         42 . A method of producing a crosslinked cyclodextrin polymer comprising the step of:
 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 oxidized cyclodextrin monomer and A is a comonomer bound to cyclodextrin monomer C,
 with a polymer in the presence of a crosslinking agent. 
 
     
     
         43 . A method of  claim 42 , wherein said polymer is a linear cyclodextrin copolymer or a linear oxidized cyclodextrin copolymer. 
     
     
         44 . A method of treatment comprising the step of administering a therapeutically effective amount of a therapeutic composition of  claim 18 . 
     
     
         45 . A method of treatment comprising the step of administering a therapeutically effective amount of a therapeutic composition of  claim 23 .