Method of formation of shape-retentive aggregates of gel particles and their uses

Abstract

The present invention relates to a method of forming shape-retentive aggregates of gel particles in which the aggregates are held together by non-covalent bond physical forces such as, without limitation, hydrophobic-hydrophilic interactions and hydrogen bonds. The method comprises introducing a suspension of gel particles in a polar liquid at a selected concentration, wherein the gel particles have an absolute zeta potential, into a medium in which the absolute zeta potential of the gel particles is decreased, resulting in the gel particles coalescing into the claimed shape-retentive aggregate. This invention also relates to uses of the method of formation of the shape-retentive aggregates of gel particles.

1 . A method for forming a shape-retentive aggregate of gel particles, comprising: 
 providing a suspension system comprising a plurality of gel particles dispersed in a polar liquid or a mixture of two or more miscible liquids, at least one of which is polar, wherein the gel particles have a first absolute zeta potential; and,    introducing the suspension system through an orifice at a selected introduction rate into a receiving medium wherein the gel particles acquire a second absolute zeta potential which is lower (closer to zero) than the first absolute zeta potential whereupon the gel particles coalesce into a shape-retentive aggregate held together by non-covalent bond physical forces comprising hydrophobic-hydrophilic interactions and hydrogen bonds.    
     
     
         2 .- 53 . (canceled)  
     
     
         54 . A method for preparing a shape-retentive hydrogel aggregate composition 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;    (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 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.    
     
     
         55 . A method for preparing a shape-retentive hydrogel aggregate composition, 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.    
     
     
         56 . The method of  claim 55 , 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.  
     
     
         57 . The method of  claim 54  or  55 , 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.  
     
     
         58 . The method of  claim 54  or  55 , 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.  
     
     
         59 . The method of  claim 54  or  55 , wherein the absorbed liquid is water.  
     
     
         60 . The method of  claim 54  or  55 , wherein the non-absorbed liquid is water.  
     
     
         61 . The method of  claim 54  or  55 , wherein the absorbed and the non-absorbed liquid are water.  
     
     
         62 . The method of  claim 54  or  55 , wherein the plurality of hydrogel particles is of narrow polydispersity.  
     
     
         63 . The method of  claim 54  or  55 , wherein the one or more monomer(s) are uncharged, charged or a combination thereof.  
     
     
         64 . The method of  claim 54  or  55 , wherein the plurality of hydrogel particles comprises particles of two or more different sizes and/or two or more different monomers.  
     
     
         65 . The method of  claim 54  or  55 , wherein the cross-linking agent is an α-hydroxy acid ester.  
     
     
         66 . The method of  claim 54  or  55 , wherein the cross-linking agent is selected from the group consisting of ethylene glycol diacrylate, ethylene glycol dimethylacrylate, 1,4-dihydrooxybutane dimethacrylate, dethylene glycol dimethyacrylate, propylene glycol dimethacrylate, diethylene 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.  
     
     
         67 . The method of  claim 54  or  55 , further comprising adding a pharmaceutically active agent or a pharmaceutically acceptable excipient to the one or more liquid(s) liquid of step (a).  
     
     
         68 . The method of  claim 54  or  55 , further comprising adding a pharmaceutically active agent or a pharmaceutically acceptable excipient to the polymerized polymer suspension formed in step (c).  
     
     
         69 . The method of  claim 54  or  55 , wherein the at least one monomer is hydroxyethyl methacryate or hydroxypropyl methacrylate.  
     
     
         70 . The method of  claim 54  or  55 , wherein the polymer consists essentially of a single monomer composition.  
     
     
         71 . The method of  claim 70 , wherein the single monomer composition is selected from the group consisting of 2,3-dihydroxypropyl methacrylate, methacrylic acid, glycidyl methacrylate, hydroxyethyl methacrylate and hydroxypropyl methacrylate.  
     
     
         72 . The method of  claim 54  or  55 , wherein the hydrogel particles of step (c) have an average diameter of 20 to 1,000 nm.  
     
     
         73 . A shape-retentive hydrogel composition formed by the method of claims  54  or  55 .  
     
     
         74 . A shape retentive hydrogel aggregate composition of  claim 73  further comprising a biological active agent.  
     
     
         75 . A method for delivering a biologically active agent in vivo, comprising administering an effective amount of the composition of  claim 74  to a subject.