Ionic polymers as toxin-binding agents

Abstract

A method for treating pathogenic toxins in a mammal, such as a human, comprising treating the mammal with a therapeutically effective amount of a polymer comprising a cationic group attached to the polymer backbone. The polymer can be a homopolymer or a copolymer. In one embodiment, the polymer is a copolymer comprising a monomer having a pendant ammonium group and a hydrophobic monomer.

What is claimed is:  
     
         1 . A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a polymer characterized by a repeat unit of comprising a plurality of Formula I,  
       
         
           
           
               
               
           
         
       
       wherein R is a hydrogen atom or a methyl or ethyl group; X is a covalent bond, a carbonyl group or a CH 2  group; Y is an oxygen atom or an NH or CH 2  group; Z is an aliphatic spacer group; R 1 , R 2  and R 3  are each, independently, a hydrogen atom, a normal or branched, substituted or unsubstituted C 1 -C 24 -alkyl group, aryl or arylalkyl group; and m and n are each, independently, 1 or 0; or —N + (R 1 )(R 2 )(R 3 ) is a heteroaryl group; and A −  is a pharmaceutically acceptable anion; or a free base thereof.  
     
     
         2 . The method of  claim 1  wherein Z is a normal or branched C 2 -C 24 -alkylene group or a C 2 -C 24 -alkylene group interrupted at one or more points by a heteroatom.  
     
     
         3 . The method of  claim 2  wherein the heteroatom is a nitrogen, oxygen or sulfur atom.  
     
     
         4 . The method of  claim 3  wherein at least one of R 1 , R 2  and R 3  is an aryl group, a benzyl group or a normal or branched, substituted or unsubstituted C 1 -C 24 -alkyl group.  
     
     
         5 . The method of  claim 3  wherein R 1 , R 2  and R 3  are each hydrogen.  
     
     
         6 . The method of  claim 1  wherein the polymer is further characterized by a difunctional cross-linking monomer.  
     
     
         7 . The method of  claim 6  wherein the difunctional cross-linking monomer is selected from the group consisting of diacrylates, triacrylates and tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraaleylammonium ion.  
     
     
         8 . The method of  claim 7  wherein the difunctional cross-linking monomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, bisphenol A diacrylate and divinylbenzene.  
     
     
         9 . The method of  claim 1  wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups.  
     
     
         10 . The method of  claim 9  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —;—C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20.  
     
     
         11 . A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a polymer characterized by a repeat unit of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are each hydrogen.  
     
     
         12 . The method of  claim 11  wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups.  
     
     
         13 . The method of  claim 12  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20.  
     
     
         14 . The method of  claim 13  wherein the bridging units are —CH 2 —CH(OH)—CH 2 —.  
     
     
         15 . A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a polymer characterized by a first repeat unit of Formula III,  
       
         
           
           
               
               
           
         
       
       wherein both R 1  and R 2  are hydrogen; and a second repeat unit of Formula III wherein R 1  and R 2  are each, independently, a C 1 -C 24 -alkyl group.  
     
     
         16 . The method of  claim 15  wherein in the second repeat unit of Formula III, R 1  is a methyl group and R 2  is a linear or branched C 1 -C 18  alkyl group.  
     
     
         17 . The method of  claim 15  wherein the polymer is cross-linked.  
     
     
         18 . The method of  claim 11  wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups.  
     
     
         19 . The method of  claim 12  wherein the bridging units are selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20.  
     
     
         20 . The method of  claim 19  wherein the polymer is further characterized by a difunctional cross-linking monomer.  
     
     
         21 . The method of  claim 20  wherein the difunctional cross-linking monomer is selected from the group consisting of diacrylates, triacrylates and tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraalylammoniumion.  
     
     
         22 . The method of  claim 21  wherein the difunctional cross-linking monomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, bisphenol A diacrylate and divinylbenzene.  
     
     
         23 . A method for inhibiting a pathogenic toxin in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a cross-linked polymer, wherein said cross-linked polymer comprises first and second polymer strands connected by a linking group, wherein: 
 said first polymer strand is characterized by a repeat unit having a primary amino group or a secondary amino group; and    said second polymer strand is characterized by a repeat unit having a tertiary amino group or a quaternary ammonium group.    
     
     
         24 . The method of  claim 23  wherein the second polymer strand is further characterized by a repeat unit having primary or secondary amino groups.  
     
     
         25 . The method of  claim 23  wherein the first polymer strand is selected from the group consisting of polyallylamine, polyvinylamine, poly(ethyleneimine), polydiallylamine, poly(N-alkylallylamine), and poly(N-alkylvinylamine).  
     
     
         26 . The method of  claim 25  wherein the first polymer strand is poly(N-methylallylamine) or poly(N-methylvinylamine).  
     
     
         27 . The method of  claim 24  wherein the second polymer strand is a copolymer characterized by a first repeat unit selected from the group consisting of N-alkyldiallylamine, N,N-dialkylallylamonium A-, N,N-dialkylallylamine, and N,N,N-trialkylallylammonium A-, wherein A- is an anion, and a second repeat unit selected from the group consisting of allylamine, vinylamine, diallylamine, N-alkylallylamine and N-alkylvinylamine.  
     
     
         28 . The method of  claim 27  wherein the second polymer strand is poly(N-alkyldiallylamine-co-diallylamine); poly(N,N-dialkyldiallylamonium-co-allylamine) A-; poly(N,N-dialkylallylamine-co-allylamine); poly(N,N-dialkylallylamine-co-N-alkylallylamine); poly(N,N,N-trialkylallylammonium-co-allylamine) A-; poly(N,N,N-trialkylallylammonium-co-N-alkylallylamine) A-; poly(N,N-dialkylvinylamine-co-vinylamine); poly(N,N-dialkylvinylamine-co-N-alkylvinylamine); poly(N,N,N-trialkylvinylammonium-co-vinylamine) A-; or poly(N,N,N-trialkylvinylammonium-co-N-alkylvinylamine) A-.  
     
     
         29 . The method of  claim 23  wherein the first polymer strand and the second polymer strand are connected by a bridging group selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups.  
     
     
         30 . The method of  claim 29  wherein the bridging unit is selected from the group consisting of —(CH 2 ) n —, wherein n is an integer from about 2 to about 20; —CH 2 —CH(OH)—CH 2 —; —C(O)CH 2 CH 2 C(O)—; —CH 2 —CH(OH)—O—(CH 2 ) m —O—CH(OH) —CH 2 —, wherein m is 2 to about 4; —C(O)—(C 6 H 2 (COOH) 2 )—C(O)—; and —C(O)NH(CH 2 ) p NHC(O)—, wherein p is an integer from about 2 to about 20.  
     
     
         31 . The method of  claim 23  wherein the cross-linked polymer is produced by a method comprising the step of contacting a mixture comprising the first linear polymer and the second linear polymer with a crosslinking agent having two or more functional groups which react with amine groups to form a covalent bond, under conditions sufficient for cross-linking of the first linear polymer and the second linear polymer.  
     
     
         32 . The method of  claim 31  wherein the crosslinking agent is selected from the group consisting of epihalohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride, dihaloalkanes and a,w-alkylene diisocyanates.  
     
     
         33 . The method of  claim 1  wherein the pathogenic toxin is produced by one or more bacteria.  
     
     
         34 . The method of  claim 33  wherein the one or more bacteria is selected from the group consisting of  E. coli  or  C. difficile.    
     
     
         35 . The method of  claim 1  wherein the pathogenic toxin is produced by one or more viruses.  
     
     
         36 . The method of  claim 1  wherein the pathogenic toxin is produced by one or more protozoa.  
     
     
         37 . The method of  claim 1  wherein the pathogenic toxin is produced by one or more fungus.