Shape-retentive hydrogel particle aggregates and their uses

Abstract

The present invention is related to hydrogel particles and aggregates formed therefrom having characteristics including, without limitation, shape-retentiveness, elasticity, controllable pore sizes and controllable degradation rates that render them useful for a wide variety of applications including, without limitation, the controlled release of biologically active substances, in vivo medical devices, tissue growth scaffolding and tissue replacement.

1 . A shape-retentive aggregate, comprising:
 a plurality of hydrogel particles, each particle comprising:
 a plurality of polymeric strands obtained by polymerization of one or more monomers at least one of which comprises one or more hydroxyl and/or one or more ether groups; 
 from 10 to 90 weight percent of one or more absorbed liquid(s), at least one of which comprises one or more hydroxyl groups, wherein the liquid(s) is/are absorbed into the hydrogel particles; 
   and,   from 10 to 90 weight percent of one or more non-absorbed liquids, which may be the same as, or different from, the absorbed liquid(s) and at least one of which comprises one or more hydroxy groups, the non-absorbed liquid occupying voids between the hydrogel particles of the aggregate.   
     
     
         2 - 70 . (canceled) 
     
     
         71 . A shape-retentive hydrogel aggregate composition formed by the method comprising:
 (a) adding a monomer or two or more different monomers selected from the group consisting of a 2-alkenoic acid, a hydroxy(2C-4C)alkyl 2-alkenoate, a hydroxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate, a (1C-4C)alkoxy(2C-4C)alkoxy(2C-4C)alkyl 2-alkenoate and a vicinyl epoxy(1C-4C)alkyl 2-alkenoate to one or more liquid(s) having one or more hydroxyl groups; and   (b) adding from 0.1 to 15 mole percent of a cross-linking agent and from 0.01 to 10 mol percent of a surfactant to the liquid(s); and   (c) polymerizing the monomers to form a suspension in the liquid(s) of a plurality of hydrogel particles comprising a plurality of polymeric strands, wherein the hydrogel particles have an average diameter of less than 1,000 nanometers, and from 10 to 90% of absorbed liquids(s); and   (d) removing non-absorbed liquids until the plurality of hydrogel particles coalesce into a shape-retentive aggregate held together by non-covalent inter-particle and particle-liquid physical forces, thereby forming a shape-retentive hydrogel aggregate composition.   
     
     
         72 . A shape-retentive hydrogel aggregate composition formed by the method comprising:
 (a) adding a monomer or two or more different monomers selected from the group consisting of acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, 2-hydroxyethylmethacrylate, diethyleneglycol monoacrylate, diethyleneglycol monomethacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methyacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monoacrylate, dipropylene glycol monomethacrylate, 2,3-dihydroxypropyl methacrylate, glycidyl acrylate and glycidyl methacrylate, to one or more liquid(s), having one or more hydroxyl groups;   (b) adding from 0.1 to 15 mole percent of a cross-linking agent and from 0.01 to 10 mol percent of a surfactant to the liquid(s);   (c) polymerizing the monomers to form a suspension in the liquid(s) of a plurality of hydrogel particles comprising a plurality of polymeric strands, wherein the plurality of hydrogel particles have an average diameter of less than 1,000 nanometers, and from 10 to 90% of absorbed liquids(s); and   (d) removing non-absorbed liquid(s) until the hydrogel particles coalesce into a shape-retentive aggregate held together by non-covalent inter-particle and particle-liquid physical forces, thereby forming a shape-retentive hydrogel aggregate composition.   
     
     
         73 . The aggregate of  claim 71 , wherein the one or more monomers are selected from the group consisting of 2-hydroxyethyl methacrylate, methyacrylic acid, 2-aminoethylmethacrylate, trimethylaminoethyl-methacrylate, glycerol methacrylate, 2-methoxyethyl methacrylate, glycidyl methacrylate, and hydroxypropyl methacrylate. 
     
     
         74 . The aggregate of  claim 71  or  72 , wherein the absorbed and non-absorbed liquids are independently selected from the group consisting of water, a (1C-10C) alcohol, a (2C-8C)polyol, a (1C-4C)alkyl ether of a (2C-8C)polyol, a (1C-4C)acid ester of a (2C-8C)polyol; a hydroxy-terminated polyethylene oxide, a polyalkylene glycol and a hydroxy(2C-4C)alkyl ester of a mono, di- or tricarboxylic acid. 
     
     
         75 . The aggregate of  claim 71  or  72 , wherein the absorbed and the non-absorbed liquids are independently selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 200-600, propylene glycol, dipropylene glycol, 1,4-butanediol, 2,3-butanediol, 1,6-hexanediol, 2,5-hexanediol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, methylcellosolve ether, ethylene glycol monoacetate, propylene glycol monomethyl ether, glycerine, glycerol monoacetate, tri(2-hydroxyethyl)citrate, di(hydroxypropyl)oxalate, glyceryl diacetate, and glyceryl monobutyrate. 
     
     
         76 . The aggregate of  claim 71  or  72 , wherein the absorbed liquid is water. 
     
     
         77 . The aggregate of  claim 71  or  72 , wherein the non-absorbed liquid is water. 
     
     
         78 . The aggregate of  claim 71  or  72 , wherein the absorbed and the non-absorbed liquid are water. 
     
     
         79 . The aggregate of  claim 71  or  72 , wherein the plurality of hydrogel particles is of narrow polydispersity. 
     
     
         80 . The aggregate of  claim 71  or  72 , wherein the one or more monomer(s) are uncharged, charged or a combination thereof. 
     
     
         81 . The aggregate of  claim 71  or  72 , wherein the plurality of hydrogel particles comprises particles of two or more different sizes and/or two or more different monomers. 
     
     
         82 . The aggregate of  claim 71  or  72 , wherein the cross-linking agent is an α-hydroxy acid ester. 
     
     
         83 . The aggregate of  claim 71  or  72 , wherein the cross-linking agent is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethylacrylate, 1,4-dihydroxybutane dimethacrylate, diethylene glycol dimethyacrylate, propylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene gycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyltoluene, diallyl tartrate, diallyl malate, divinyl tartrate, triallyl melamine, N,N′-methylene bisacryalamide, diallyl maleate, divinyl ether, 1,3-diallyl 2-(2-hydroxyethyl) citrate, vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, di(2-hydroxyethyl) itaconate, divinyl sulfone, hexahydro-1,3,5-triallyltriazine, triallyl phosphite, diallyl benzenephosphonate, triallyl aconitate, divinyl citraconate, trimethylolpropane trimethacrylate and diallyl fumarate. 
     
     
         84 . The aggregate of  claim 71  or  72 , further comprising adding a pharmaceutically active agent or a pharmaceutically acceptable excipient to the one or more liquid(s) of step (a). 
     
     
         85 . The aggregate of  claim 71  or  72 , further comprising adding a pharmaceutically active agent or a pharmaceutically acceptable excipient to the polymerized polymer suspension formed in step (c). 
     
     
         86 . The aggregate of  claim 71  or  72 , wherein the at least one monomer is hydroxyethyl methacryate or hydroxypropyl methacrylate. 
     
     
         87 . The aggregate of  claim 71  or  72 , wherein the polymer consists essentially of a single monomer composition. 
     
     
         88 . The aggregate of  claim 87 , wherein the single monomer composition is selected from the group consisting of methacrylic acid, glycidyl methacrylate, hydroxyethyl methacrylate, 2,3-dihydroxypropyl methacrylate and hydroxypropyl methacrylate. 
     
     
         89 . The aggregate of  claim 71  or  72 , wherein the hydrogel particles of step (c) have an average diameter of 20 to 1,000 nm. 
     
     
         90 . A composition comprising the shape-retentive hydrogel aggregate of  claim 71  or  72  and a biologically active agent. 
     
     
         91 . A method for delivering a biologically active agent in vivo, comprising administering the composition of  claim 90  to a subject.