Degradable poly(ethylene glycol) hydrogels with controlled half-life and precursors therefor

Abstract

This invention relates to hydrolytically degradable gels of crosslinked poly(ethylene) glycol (PEG) structures. Addition of water causes these crosslinked structures to swell and become hydrogels. The hydrogels can be prepared by reacting two different PEG derivatives containing functional moieties at the chain ends that react with each other to form new covalent linkages between polymer chains. The PEG derivatives are chosen to provide covalent linkages within the crosslinked structure that are hydrolytically degradable. Hydrolytic degradation can provide for dissolution of the gel components and for controlled release of trapped molecules, including drugs. Reagents other than PEG can be avoided. The hydrolysis rates can be controlled by varying atoms adjacent to the hydrolytically degradable functional groups to provide substantially precise control for drug delivery in vivo.

What is claimed is:  
     
         1 . A crosslinked polymeric structure comprising poly(ethylene glycol) (PEG) polymers in the substantial absence of non-PEG polymers and having linkages between said PEG polymers wherein at least some of said linkages comprise hydrolytically unstable linkages.  
     
     
         2 . The crosslinked polymeric structure of  claim 1  wherein said hydrolytically unstable linkages are sufficient to cause said crosslinked polymeric structure to degrade by hydrolysis in aqueous solution.  
     
     
         3 . The crosslinked polymeric structure of  claim 1  wherein said structure forms a PEG hydrogel in aqueous solution that is subject to hydrolysis.  
     
     
         4 . The crosslinked polymeric structure of  claim 3  wherein the PEG hydrogel formed therefrom has a rate of hydrolysis that is determined at least in part by the structure of said linkages between said PEG polymers.  
     
     
         5 . The crosslinked polymeric structure of  claim 4  wherein said linkages comprise one or more methylene groups in proximity to said hydrolytically unstable linkages sufficient to determine at least in part said rate of hydrolysis of said hydrolytically unstable linkages.  
     
     
         6 . The crosslinked polymeric structure of  claim 5  wherein said hydrolysis rate is decreased as the number of said methylene groups is increased.  
     
     
         7 . The crosslinked polymeric structure of  claim 1  wherein said hydrolytically unstable linkages comprise linkages selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides.  
     
     
         8 . The crosslinked polymeric structure of  claim 7  wherein said hydrolytically unstable ester linkages comprise linkages selected from the group consisting of carboxylate esters and phosphate esters.  
     
     
         9 . The crosslinked polymeric structure of  claim 8  wherein said hydrolytically unstable carboxylate ester linkages are the reaction product of a PEG alcohol and a PEG carboxylic acid and wherein said hydrolytically unstable phosphate ester linkages are the reaction product of a PEG alcohol and a PEG phosphate.  
     
     
         10 . The crosslinked polymeric structure of  claim 7  wherein said imines are the reaction product of an amine and an aldehyde, wherein said hydrazones are the reaction product of a hydrazide and an aldehyde, wherein said acetals are the reaction product of an aldehyde and an alcohol, wherein said orthoesters are the reaction product of a formate and an alcohol, wherein said hydrolytically unstable peptide linkages comprise linkages selected from the group consisting of peptide linkages that are the reaction product of amines and PEG-peptide conjugates terminated with carboxyl and peptide linkages that are the reaction product of a carboxylic acid and PEG-peptide conjugates terminated with amine, and wherein said hydrolytically unstable oligonucleotide linkages are the reaction product of a phosphoramidite with a 5′-hydroxyl-terminated PEG oligonucleotide.  
     
     
         11 . The crosslinked polymeric structure of  claim 1  wherein said structure also comprises hydrolytically stable linkages that do not degrade in aqueous solution.  
     
     
         12 . The crosslinked polymeric structure of  claim 11  wherein said hydrolytically stable linkages comprise linkages selected from the group consisting of amides, urethanes, ureas, amines, and sulfonamides.  
     
     
         13 . The crosslinked polymeric structure of  claim 12  wherein said amide linkages are the reaction product of an ester and an amine, wherein said urethane linkages are the reaction product of an isocyanate and an alcohol, wherein said urea linkages are the reaction product of an isocyanate and an amine, wherein said hydrolytically stable amine linkages are selected from the group consisting of the reaction product of an aldehyde and an amine in the presence of a reducing agent and the reaction product of an epoxide and an amine, and wherein said sulfonamide linkages are the reaction product of an amine and a sulfonate ester.  
     
     
         14 . The crosslinked polymeric structure of  claim 13  wherein said amide linkages are the reaction product of a carboxylate ester and an amine.  
     
     
         15 . A drug delivery system comprising a poly(ethylene glycol) hydrogel made from the crosslinked polymeric structure of  claim 1 .  
     
     
         16 . A poly(ethylene glycol) (PEG) hydrogel comprising PEG polymers in the substantial absence of non-PEG polymers and having linkages between said PEG polymers wherein at least some of said linkages are hydrolyzable under hydrolysis conditions, said hydrolyzable linkages comprising linkages selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides.  
     
     
         17 . A drug delivery system comprising the PEG hydrogel of  claim 15 .  
     
     
         18 . A crosslinked polymeric structure comprising poly(ethylene glycol) (PEG) and having a formula selected from the group consisting of:  
       {R[CH 2 —O-PEG-W-PEG-W-] p } m  {R[CH 2 —O-PEG-X-PEG-W-PEG-X-] p } m  {R[CH 2 —O-PEG-X-R′-W-PEG-W-R′-X-] p } m    
       wherein m means “matrix” and indicates that the crosslinked structure is a solid aggregate; p is from about 3 to 10 and indicates the number of arms on the polymers forming said crosslinked structure; R is a central branching moiety suitable for making multiarmed PEGs; R′ is a hydrocarbon fragment having from about 1 to 10 carbons; W is a hydrolytically unstable linkage comprising linkages selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides; and X is a hydrolytically stable linkage comprising linkages selected from the group consisting of amides, urethanes, ureas, amines, and sulfonamides.  
     
     
         19 . The crosslinked polymeric structure of  claim 18  wherein R is a moiety selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, trimethyolpropane, and di(trimethylolpropane).  
     
     
         20 . The crosslinked polymeric structure of  claim 18  wherein said hydrolytically unstable linkages W comprise carboxylate ester linkages that are the reaction product of an alcohol and a carboxylic acid; phosphate ester linkages that are the reaction product of an alcohol and a phosphate, imine linkages that are the reaction product of an amine and an aldehyde; hydrazones linkages that are the reaction product of a hydrazide and an aldehyde; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; peptide linkages that comprise linkages selected from the group consisting of peptide linkages that are the reaction product of amines and PEG-peptide conjugates terminated with carboxyl and peptide linkages that are the reaction product of a carboxylic acid and PEG-peptide conjugates terminated with amine; and oligonucleotide linkages that are the reaction product of a phosphoramidite with a 5′-hydroxyl-terminated PEG oligonucleotide.  
     
     
         21 . The crosslinked polymeric structure of  claim 18  wherein said hydrolytically stable linkages X comprise amide linkages that are the reaction product of an ester and an amine; urethane linkages that are the reaction product of an isocyanate and an alcohol; urea linkages that are the reaction product of an isocyanate and an amine; amine linkages that are selected from the group consisting of the reaction product of an aldehyde and an amine in the presence of a reducing agent and the reaction product of an epoxide and an amine; and sulfonamide linkages that are the reaction product of an amine and a sulfonate ester.  
     
     
         22 . The crosslinked polymeric structure of  claim 21  wherein said amide linkages are the reaction product of a carboxylate ester and an amine.  
     
     
         23 . A drug delivery system comprising a poly(ethylene glycol) hydrogel made from the crosslinked polymeric structure of  claim 18 .  
     
     
         24 . A crosslinked polymeric structure comprising poly(ethylene glycol) (PEG) and having the formula:  
       {R[CH 2 —O-PEG-O 2 C—(CH 2 ) n —O-PEG-O(CH 2 ) n —CO 2 —] p } m    
       wherein m means “matrix” and indicates that the crosslinked structure is a solid aggregate; p is from about 3 to 10 and indicates the number of arms on the polymers forming said crosslinked structure; R is a moiety selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, trimethyolpropane, and di(trimethylolpropane); and wherein n is from about 1 to 10.  
     
     
         25 . A crosslinked polymeric structure comprising poly(ethylene glycol) (PEG) and having the formula:  
       {CH 3 C[CH 2 —O-PEG-O 2 C—(CH 2 ) n —O-PEG-O(CH 2 ) n —CO 2 —] p } m    
       wherein m means “matrix” and indicates that the crosslinked structure is a solid aggregate, and wherein n is from about 1 to 10.  
     
     
         26 . The crosslinked polymeric structure of  claim 25  wherein when n equals 2, then the ester linkages have a hydrolysis half life of about 4 days at pH 7 and 37 degrees Centrigrade, and wherein when n equals 3, then the ester linkages have a hydrolysis half life of about 43 days at pH 7 and 37 degrees Centrigrade.  
     
     
         27 . A method of making a crosslinked polymeric structure comprising poly(ethylene glycol) (PEG) polymers in the substantial absence of non-PEG polymers and having linkages between said PEG polymers wherein at least some of said linkages comprise hydrolytically unstable linkages, said method comprising reacting a linear poly(ethylene glycol) (PEG) with a branched PEG to provide a crosslinked structure having linkages between said PEG polymers wherein at least some of said linkages comprise hydrolyzable linkages.  
     
     
         28 . The method of  claim 27  wherein the step of reacting a linear PEG with a branched PEG includes the steps of separately injecting the linear PEG and the branched PEG into a living organism or into a substance taken from a living organism in close proximity in time and space and reacting the linear and branched PEGs in vivo to form a hydrogel.  
     
     
         29 . A method for delivering biologically active substances to a living organism or to a substance taken from a living organism comprising mixing at least one biologically active substance with a linear PEG or a branched PEG as set forth in  claim 28 , separately injecting the linear PEG and the branched PEG into a living organism or into a substance taken from a living organism in close proximity in time and space, reacting the linear and branched PEGs in vivo to form a degradable hydrogel matrix in which the biologically active substance is trapped, and subjecting the hydrogel to hydrolysis to degrade the hydrogel and allow the biologically active substances to be delivered.  
     
     
         30 . A method for making a crosslinked polymeric structure comprising reacting. a linear poly(ethylene glycol) (PEG) polymer of the formula Z-PEG-Z with a branched PEG polymer of the formula R(CH 2 —O-PEG-Y) p  to provide a crosslinked structure of the formula {R[CH 2 —O-PEG-W-PEG-] p } m , wherein m means “matrix” and indicates that the crosslinked structure is a solid aggreagte; p is from about 3 to 10 and indicates the number of arms on the polymers forming said crosslinked structure; R is a central branching moiety suitable for making multiarmed PEGs, and wherein Z reacts with Y to form the hydrolytically unstable group W, and Z and Y are selected from the group consisting of alcohols, carboxylic acids, amines, aldehydes, hydrazides, aldehydes, phosphate, formate, PEG-peptide terminated with carboxyl, PEG-peptide terminated with amine, PEG phosphoramidite, and 5′-hydroxyl-terminated PEG oligonucleotide, and wherein W is selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides.  
     
     
         31 . A method for making a crosslinked polymeric structure comprising reacting a linear poly(ethylene glycol) (PEG) with a branched PEG polymer according to the following equation:  
       U-PEG-W-PEG-U+R(CH 2 —O-PEG-V) p →→{[CH 2 —O-PEG-X-PEG-W-PEG-X-] p } m    
       wherein W is selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides; wherein U reacts with V to form X, and U and V are selected from the group consisting of active esters, amine, isocyanate, aldehyde, epoxide, and sulfonate ester; wherein X is selected from the group consisting of amides, urethanes, ureas, amines, and sulfonamides; and wherein m means “matrix” and indicates that the crosslinked structure is a solid aggreagte; p is from about 3 to 10 and indicates the number of arms on the polymers forming said crosslinked structure; and R is a central branching moiety suitable for making multiarmed PEGs.  
     
     
         32 . A method for making a crosslinked polymeric structure comprising reacting a linear poly(ethylene glycol) (PEG) with a branched PEG polymer according to the following equation:  
       U-R′-W-PEG-W-R′-U+R(CH 2 —O-PEG-V) p →{R[CH 2 —O-PEG-X-R′-W-PEG-W-R′-X] p } m    
       wherein R′ is a hydrocarbon fragment having from about 1 to 10 carbons; wherein W is selected from the group consisting of esters, imines, hydrazones, acetals, orthoesters, peptides, and oligonucleotides; wherein U reacts with V to form X, and U and V are selected from the group consisting of active esters, amine, isocyanate, aldehyde, epoxide, and sulfonate ester; wherein X is selected from the group consisting of amides, urethanes, ureas, amines, and sulfonamides; and wherein m means “matrix” and indicates that the crosslinked structure is a solid aggreagte; p is from about 3 to 10 and indicates the number of arms on the polymers forming said crosslinked structure; and R is a central branching moiety suitable for making multiarmed PEGs.