Biocompatible crosslinked polymers

Abstract

Biocompatible crosslinked polymers, and methods for their preparation and use, are disclosed in which the biocompatible crosslinked polymers are formed from water soluble precursors having electrophilic and nucleophilic groups capable of reacting and crosslinking in situ. Methods for making the resulting biocompatible crosslinked polymers biodegradable or not are provided, as are methods for controlling the rate of degradation. The crosslinking reactions may be carried out in situ on organs or tissues or outside the body. Applications for such biocompatible crosslinked polymers and their precursors include controlled delivery of drugs, prevention of post-operative adhesions, coating of medical devices such as vascular grafts, wound dressings and surgical sealants.

1 . Method of making a biocompatible degradable hydrogel to treat a medical condition comprising: 
 identifying a medical condition for treatment by use of a hydrogel formed in situ in a patient and essentially fully degradable in a patient in less than about 180 days; and    selecting precursors to form the hydrogel for treatment of the medical condition, the selection of the precursors comprising:    selecting a first biocompatible precursor having a water solubility of at least 1 gram per 100 milliliters and at least two electrophilic functional groups;    selecting a second biocompatible precursor comprising at least two nucleophilic amine functional groups;    selecting one of (i), (ii), or (iii), wherein 
 (i) the first precursor is selected have only one or two hydrolytically degradable ester bonds per every electrophilic functional group on the precursor, or  
 (ii) the second precursor is selected to have only one or two hydrolytically degradable ester bonds per every nucleophilic functional group on the precursor, or  
 (iii) selecting both (i) and (ii);  
   and selecting the electrophilic and nucleophilic groups to form covalent bonds that are reaction products of the electrophilic and nucleophilic groups, wherein essentially every ester bond in the hydrogel is separated from other ester bonds in the hydrogel by at least three covalent bonds when the hydrogel is formed.    
     
     
         2 . The method of  claim 1  wherein the medical condition is adhesion prevention.  
     
     
         3 . The method of  claim 1  wherein the medical condition is tissue adhesion.  
     
     
         4 . The method of  claim 1  wherein the medical condition is drug delivery.  
     
     
         5 . The method of  claim 1  wherein the medical condition is wound covering.  
     
     
         6 . The method of  claim 1  wherein the medical condition is tissue sealing.  
     
     
         7 . The method of  claim 1  wherein the medical condition is tissue coating.  
     
     
         8 . The method of  claim 1  wherein the solids concentration of the hydrogel ranges from 8.5% to 20% w/w.  
     
     
         9 . The method of  claim 1  wherein the second precursor has a molecular weight of less than about 1000.  
     
     
         10 . The method of  claim 1  wherein the first precursor comprises carboxymethyl-hydroxybutyrate-N-hydroxysuccinimidyl polyethylene glycol.  
     
     
         11 . The method of  claim 1  wherein the first precursor comprises succinimidyl glutarate.  
     
     
         12 . The method of  claim 1  wherein the electrophilic functional groups of the first precursor comprise n-hydroxysuccinimide ester.  
     
     
         13 . The method of  claim 1  wherein the electrophilic functional groups of the first precursor comprise a member of the group consisting of carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimide ester, epoxide, aldehyde, maleimides and imidoester.  
     
     
         14 . The method of  claim 1  wherein the second precursor consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetalysine.  
     
     
         15 . The method of  claim 1  wherein at least one of the precursors is selected to further comprise a chemical group having the formula (CH 2 CH 2 O) n .  
     
     
         16 . The method of  claim 1  wherein the second precursor comprises a lysine.  
     
     
         17 . The method of  claim 1  wherein the hydrogel is essentially fully degradable in a patient in less than about 90 days.  
     
     
         18 . The method of  claim 1  wherein the hydrogel is essentially fully degradable in a patient in less than about 45 days.  
     
     
         19 . A method of making a biocompatible readily degradable hydrogel comprising: 
 providing a first biocompatible precursor having a water solubility of at least 1 gram per 100 milliliters, at least two electrophilic functional groups, and no more than two hydrolytically degradable ester bonds per electrophilic functional group;    providing a second biocompatible precursor comprising at least two nucleophilic functional groups and no more than two hydrolytically degradable ester bonds per nucleophilic functional group;    wherein at least one of the precursors is selected to have one or two hydrolytically degradable ester bonds per electrophilic functional group;    selecting the nucleophilic groups and the electrophilic groups to form a hydrogel essentially fully degradable in vivo in less than about 180 days, wherein the nucleophilic groups are amines; and    mixing the precursors to form a covalently crosslinked hydrogel, wherein essentially every ester bond in the hydrogel is separated from other ester bonds in the hydrogel by at least three covalent bonds when the hydrogel is formed.    
     
     
         20 . The method of  claim 19  wherein the solids concentration of the hydrogel ranges from 8.5% to 20% w/w.  
     
     
         21 . The method of  claim 19  wherein the first precursor comprises carboxymethyl-hydroxybutyrate-N-hydroxysuccinimidyl polyethylene glycol.  
     
     
         22 . The method of  claim 19  wherein the second precursor has a molecular weight of less than about 1000.  
     
     
         23 . The method of  claim 22  wherein the second precursor consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetralysine.  
     
     
         24 . The method of  claim 19  wherein the first precursor comprises succinimidyl glutarate.  
     
     
         25 . The method of  claim 24  wherein the second precursor consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetralysine.  
     
     
         26 . The method of  claim 19  wherein the electrophilic functional groups of the first precursor comprise n-hydroxysuccinimide ester.  
     
     
         27 . The method of  claim 19  wherein the electrophilic functional groups of the first precursor comprise a member of the group consisting of carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimide ester, epoxide, aldehyde, maleimides and imidoester.  
     
     
         28 . The method of  claim 27  wherein the second precursor consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetralysine.  
     
     
         29 . The method of  claim 19  wherein the second precursor comprises a lysine.  
     
     
         30 . The method of  claim 19  wherein at least one of the precursors is selected to further comprise a chemical group having the formula (CH 2 CH 2 O) n .  
     
     
         31 . The method of  claim 19  wherein the hydrogel is degradable vivo in less than about 90 days.  
     
     
         32 . The method of  claim 19  wherein the hydrogel is degradable in vivo in less than about 45 days.  
     
     
         33 . A biocompatible degradable material in a product, the material comprising: 
 a hydrogel comprising a first biocompatible precursor crosslinked with a second biocompatible precursor,    wherein the first precursor, before crosslinking, comprises polyethylene glycol and a member of the group consisting of succinimidyl glutarate, carboxymethyl-hydroxybutyrate-N-hydroxysuccinimide, carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimide ester, epoxide, aldehyde, maleimides and imidoester,    wherein the second biocompatible precursor, before crosslinking, is a member of the group consisting of lysine, dilysine, trilysine, and tetralysine,    wherein the hydrogel forms a product essentially fully degradable in less than about 180 days, and the product is a member of the group consisting of adhesion prevention, tissue adhesion, drug delivery, wound covering, tissue sealing, and tissue coating.    
     
     
         34 . A biocompatible readily degradable material in a product, the material comprising: 
 a hydrogel comprising a first biocompatible precursor crosslinked with a second biocompatible precursor,    wherein the first precursor, before crosslinking, comprises succinimidyl glutarate,    wherein the second biocompatible precursor, before crosslinking, consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetralysine,    wherein the hydrogel forms a product essentially fully degradable in less than about 180 days, and the product is a member of the group consisting of adhesion prevention, tissue adhesion, drug delivery, wound covering, tissue sealing, and tissue coating.    
     
     
         35 . A biocompatible readily degradable hydrogel article comprising: 
 a hydrogel article comprising a first biocompatible precursor crosslinked with a second biocompatible precursor,    wherein the first precursor, before crosslinking, comprises at least two amines and no more than one hydrolytically degradable ester group per amine,    wherein the second precursor, before crosslinking, comprises at least two electrophiles and no more than one hydrolytically degradable ester group per electrophile,    wherein at least one of the precursors has at least one hydrolytically degradable ester, and essentially every ester bond in the hydrogel article is separated from other ester bonds in the hydrogel by at least three covalent bonds when the hydrogel is formed, with the ester bonds being hydrolytically degradable so that the hydrogel article is essentially fully hydrolytically degradable in physiological conditions in less than about 180 days    and the hydrogel article is a member of the group consisting of an adhesion prevention hydrogel article, a tissue adhesion hydrogel article, a drug delivery hydrogel article, a wound covering hydrogel article, a tissue sealing hydrogel article, and a tissue coating hydrogel article.    
     
     
         36 . The hydrogel article of  claim 35  wherein the hydrogel article is essentially fully hydrolytically degradable in physiological conditions in less than about 90 days.  
     
     
         37 . The hydrogel article of  claim 35  wherein the hydrogel article is essentially fully hydrolytically degradable in physiological conditions in less than about 45 days.  
     
     
         38 . The hydrogel article of  claim 35  wherein the hydrogel article is essentially fully hydrolytically degradable in physiological conditions in less than about 10 days.  
     
     
         39 . The hydrogel article of  claim 35  wherein the solids concentration of the hydrogel ranges from 8.5% to 20% w/w.  
     
     
         40 . The hydrogel article of  claim 35  wherein the first precursor has a molecular weight of less than about 1000.  
     
     
         41 . The hydrogel article of  claim 35  wherein the second precursor comprises carboxymethyl-hydroxybutyrate-N-hydroxysuccinimidyl polyethylene glycol.  
     
     
         42 . The hydrogel article of  claim 35  wherein the second precursor comprises succinimidyl glutarate.  
     
     
         43 . The hydrogel article of  claim 35  wherein the electrophilic functional groups of the second precursor comprise n-hydroxysuccinimide ester.  
     
     
         44 . The hydrogel article of  claim 35  wherein the electrophilic functional groups of the second precursor comprise a member of the group consisting of carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimide ester, epoxide, aldehyde, maleimides and imidoester.  
     
     
         45 . The hydrogel article of  claim 35  wherein the first precursor consists essentially of a member of the group consisting of lysine, dilysine, trilysine, and tetralysine.  
     
     
         46 . The hydrogel article of  claim 35  wherein at least one of the precursors is selected to further comprise a chemical group having the formula (CH 2 CH 2 O) n .