Reactive polysaccharide-based hemostatic agent

Abstract

Compositions and methods related to powdered hemostats that crosslink during and/or after application to a bleeding site are generally described.

1 - 160 . (canceled) 
     
     
         161 . A dry, powdered hemostatic composition, comprising:
 a first component comprising a modified polysaccharide component comprising a plurality of polysaccharide chains functionalized with electrophilic groups capable of reacting with amine groups, wherein the first modified polysaccharide component comprises one or more modified polysaccharides chosen from:
 a) a plurality of dry, porous, microspheres formed of crosslinked starch functionalized with the electrophilic groups, and 
 b) hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups; and 
   a second component comprising a protein, wherein the first and second components are able to crosslink with each other to form a hemostatic hydrogel.   
     
     
         162 . The dry, powdered hemostatic composition of  claim 161 , wherein the electrophilic groups comprise a leaving group selected from the group consisting of: N-oxysuccinimidyl, N-oxysulfosuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl. 
     
     
         163 . The dry, powdered hemostatic composition of  claim 161 , wherein the modified polysaccharide component comprises hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups. 
     
     
         164 - 170 . (canceled) 
     
     
         171 . A dry, powdered hemostatic composition, comprising:
 a first component comprising a modified polysaccharide component comprising a plurality of polysaccharide chains functionalized with electrophilic groups capable of reacting with amine groups, wherein the first modified polysaccharide component comprises one or more modified polysaccharides chosen from:
 a) a plurality of dry, porous, microspheres formed of crosslinked starch functionalized with the electrophilic groups, and 
 b) hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups; and 
   a second component comprising a multifunctionalized polyalkylene oxide-based polymer comprising amine groups or a corresponding salt thereof, wherein the first and second components are able to crosslink with each other to form a hemostatic hydrogel.   
     
     
         172 . The dry, powdered hemostatic composition of  claim 171 , wherein the electrophilic groups comprise a leaving group selected from the group consisting of: N-oxysuccinimidyl, N-oxysulfosuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl. 
     
     
         173 . The dry, powdered hemostatic composition of  claim 171 , wherein the modified polysaccharide component comprises hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups. 
     
     
         174 - 178 . (canceled) 
     
     
         179 . The dry, powdered hemostatic composition of  claim 171 , wherein the multifunctionalized polyalkylene oxide-based polymer is a polyethylene glycol. 
     
     
         180 . The dry, powdered hemostatic composition of  claim 179 , wherein the multifunctionalized polyalkylene oxide-based polymer has the following structure:
   R 2 N—(CH 2 ) n —(O(CH 2 ) n ) m —NR 2 ,
   
       wherein each R can independently be hydrogen or branched or unbranched C 1 -C 4  alkyl, n is an integer from 1 to 6, and m is an integer from 1 to 200. 
     
     
         181 . The dry, powdered hemostatic composition of  claim 180 , wherein the multifunctionalized polyalkylene oxide-based polymer has the following structure:
   H 2 N—(CH 2 ) 2 —(O(CH 2 ) 2 ) m —NH 2 ,
   
       wherein m is an integer from 1 to 200. 
     
     
         182 - 184 . (canceled) 
     
     
         185 . A dry, powdered hemostatic composition, comprising:
 a first dry powder component comprising a plurality of modified microporous microspheres comprising hydrolyzed starch crosslinked with glycerol ether or polyglycerol ether linkages comprising at least 1,3,-oxy-propan-2-ol linkages, and functionalized with ligands comprising leaving groups selected from the group consisting of: N-oxysuccinimidyl, N-oxysulfosuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl; and   a second dry powder component comprising a protein, wherein the first and second dry powder components are able to crosslink into a hemostatic hydrogel upon exposure to water.   
     
     
         186 . A method for controlling bleeding, comprising:
 applying a dry powder comprising:   a first component comprising a modified polysaccharide component comprising a plurality of polysaccharide chains functionalized with electrophilic groups capable of reacting with amine groups, wherein the first modified polysaccharide component comprises one or more modified polysaccharides chosen from:
 a) a plurality of dry, porous, microspheres formed of crosslinked starch functionalized with the electrophilic groups, and 
 b) hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups; and 
   a second component comprising a protein,   
       to a bleeding/wound site whereupon a hemostatic hydrogel is formed via crosslinking of the first component and the second component at the bleeding/wound site able to reduce or stop bleeding at the bleeding/wound site. 
     
     
         187 . The method of  claim 186 , wherein the electrophilic groups comprise a leaving group selected from the group consisting of: N-oxysuccinimidyl, N-oxysulfosuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl. 
     
     
         188 . The method of  claim 186 , wherein the modified polysaccharide component comprises hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups. 
     
     
         189 - 191 . (canceled) 
     
     
         192 . The method of  claim 186 , wherein the protein comprises serum albumin. 
     
     
         193 - 195 . (canceled) 
     
     
         196 . A method for controlling bleeding, comprising:
 applying a dry powder comprising:   a first component comprising a modified polysaccharide component comprising a plurality of polysaccharide chains functionalized with electrophilic groups capable of reacting with amine groups, wherein the first modified polysaccharide component comprises one or more modified polysaccharides chosen from:
 a) a plurality of dry, porous, microspheres formed of crosslinked starch functionalized with the electrophilic groups, and 
 b) hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups; and 
   a second component comprising a multifunctionalized polyalkylene oxide-based polymer comprising amine groups or a corresponding salt thereof,   
       to a bleeding/wound site whereupon a hemostatic hydrogel is formed via crosslinking of the first component and the second component at the bleeding/wound site able to reduce or stop bleeding at the bleeding/wound site. 
     
     
         197 . The method of  claim 196 , wherein the electrophilic groups comprise a leaving group selected from the group consisting of: N-oxysuccinimidyl, N-oxysulfosuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl. 
     
     
         198 . The method of  claim 196 , wherein the modified polysaccharide component comprises hydrolyzed, uncrosslinked starch functionalized with the electrophilic groups. 
     
     
         199 - 203 . (canceled) 
     
     
         204 . The method of  claim 196 , wherein the multifunctionalized polyalkylene oxide-based polymer is a polyethylene glycol. 
     
     
         205 . The method of  claim 204 , wherein the multifunctionalized polyalkylene oxide-based polymer has the following structure:
   R 2 N—(CH 2 ) n —(O(CH 2 ) n ) m —NR 2 ,
   
       wherein each R can independently be hydrogen or branched or unbranched C 1 -C 4  alkyl, n is an integer from 1 to 6, and m is an integer from 1 to 200. 
     
     
         206 - 209 . (canceled) 
     
     
         210 . A method for controlling bleeding, comprising:
 applying a dry powder comprising:   a first powder component comprising a plurality of modified microporous microspheres comprising hydrolyzed starch crosslinked with glycerol ether or polyglycerol ether linkages comprising at least 1,3,-oxy-propan-2-ol linkages, and functionalized with ligands comprising leaving groups selected from the group consisting of: N-oxysuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl; and   a second dry powder component comprising a protein,   
       to a bleeding/wound site whereupon a hemostatic hydrogel is formed via crosslinking of the first component and the second component at the bleeding/wound site able to reduce or stop bleeding at the bleeding/wound site.