# US 8,772,355 B2 · Stealth polymeric particles for delivery of bioactive or diagnostic agents > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,772,355 B2 - Document ID: US8772355B2 - Status: Granted - Kind: B2 - Application number: 12/952,856 - Filed: 2010-11-23 - Published: 2012-05-24 - Granted: 2014-07-08 - Earliest claimed: 2010-11-23 - Assignees: Howard University - Applicants: Emmanuel Akala; Oluyomi Okunola - Inventors: Emmanuel Akala; Oluyomi Okunola - Web page: https://patentgrep.com/patent/US8772355B2 ## CPC - C08F 290/062: {Polyethers} - A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers} - A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides} - A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} - A61K 31/337: having four-membered rings, e.g. taxol - A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} - C08F 8/00: Chemical modification by after-treatment (graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C) - C08F 8/30: Introducing nitrogen atoms or nitrogen-containing groups - C08F 220/68: Esters - Y10T 428/2982: Particulate matter [e.g., sphere, flake, etc.] - C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION ## Abstract The present invention is directed to a crosslinked or non-crosslinked polymer particle, wherein the crosslinked polymer particle comprises a copolymer of poly(alklyene glycol-graft-acrylate) that is crosslinked by at least one hydrolysable monomer or crosslinking agent. The present invention is also directed to a polymer particle comprising a crosslinked polymer particle that is a product of starting materials comprising (a) a hydrophilic monomer, (b) a hydrophobic monomer, and (c) a hydrolysable crosslinking agent (the crosslinking agent may be absent in the case of non-crosslinked particles). The present invention is still further directed to a polymer particle comprising a crosslinked copolymer, where the crosslinked copolymer includes structures represented by Formulas (I), (II), and (III), as defined in the specification. Other embodiments of the present invention also include methods of manufacturing polymer particles. ## Claims ### Claim 1 A blend of polymeric particles comprising a polymer which comprises a copolymer of poly(alklyene glycol-graft-acrylate), which copolymer is a free radical dispersion polymerization product of polyalkylene glycol and an acrylate, the copolymer optionally crosslinked by at least one hydrolysable crosslinker, the copolymer polymerized at 0° C. to about 25° C. ### Claim 2 (depends on 1) The blend of polymeric particles of claim 1, wherein the copolymer is poly(ethylene glycol-graft-methyl methacrylate). ### Claim 3 (depends on 1) The blend of polymeric particles of claim 1, wherein the copolymer is crosslinked to provide a crosslinked copolymer. ### Claim 4 (depends on 1) The blend of polymeric particles of claim 1, wherein a ratio of alklyene glycol to acrylate is from about 12:1 to about 6:4. ### Claim 5 (depends on 1) The blend of polymeric particles of claim 1, wherein the amount of the hydrolysable crosslinker is from about 1 mol % to about 4 mol % based on the total amount of copolymer. ### Claim 6 (depends on 1) The blend of polymeric particles of claim 1, wherein the average size of the polymeric particles is from about 50 nm to about 431.6 nm. ### Claim 7 (depends on 1) The blend of polymeric particles of claim 1, wherein the polymeric particles further comprise a therapeutic agent contained in the particles. ### Claim 8 (depends on 7) The blend of polymeric particles of claim 7, wherein the therapeutic agent is selected from the group consisting of 2-chloro-3-diacetylamino-1,4-naphthoquinone, docetaxel, doxorubicin and paclitaxel. ### Claim 9 A blend of polymeric particles comprising a crosslinked copolymer which is a free radical dispersion polymerization copolymer of: a hydrophilic monomer selected from the group consisting of alkene glycol, polyalkylene glycol and mixtures thereof, a hydrophobic acrylate monomer, which copolymer is crosslinked with a hydrolysable crosslinking agent, the copolymer polymerized and crosslinked at 0° C. to about 25° C., the polymeric particles including a therapeutic agent contained in the particles. ### Claim 10 (depends on 9) The blend of polymeric particles of claim 9, wherein the hydrophilic monomer is a poly(ethylene glycol)monomethyl ether mono methacrylate. ### Claim 11 (depends on 9) The blend of polymeric particles of claim 9, wherein the hydrophobic monomer is methyl methacrylate. ### Claim 12 (depends on 9) The blend of polymeric particles of claim 9, wherein the hydrolysable crosslinking agent is selected from the group consisting of N,O-dimethylacryloylhydroxylamine, di(2-acryloyloxy ethoxy)-[4-hydroxyphenyl]methane, ethylene glycol dimethacrylate, 4,4′-di(methacryloylamino)azobenzene, N,N′-methylenebisacrylamide, tetraethylene glycol dimethacrylate, ethylene glycol divinyl carbonate, and methacryloxyethyl vinyl carbonate. ### Claim 13 (depends on 9) The blend of polymeric particles of claim 9, wherein a ratio of the hydrophilic monomer to the hydrophobic monomer is from about 12:1 to about 6:4. ### Claim 14 (depends on 9) The blend of polymeric particles of claim 9, wherein the amount of hydrolysable crosslinking agent is from about 1 mol % to about 4 mol % based on the total amount of the hydrophilic monomer and the hydrophilic monomer. ### Claim 15 (depends on 9) The blend of polymeric particles of claim 9, wherein the average size is from about 50 nm to about 431.6 nm. ### Claim 16 (depends on 9) The blend of polymeric particles of claim 9, wherein the therapeutic agent is selected from the group consisting of 2-chloro-3-diacetylamino-1,4-naphthoquinone, docetaxel, doxorubicin and paclitaxel. ### Claim 17 A blend of polymeric particles comprising a polymer which is a free radical dispersion polymerization copolymer polymerized at 0° C. to about 25° C. and made from at least three monomers which provide the copolymer including structures represented by Formulas (I), (II), and (III): wherein R1-R5 each represent a group, which may be the same or different from each other, and the group is selected from the group consisting of a hydrogen, a halogen, and an alkyl group having one to five carbon atoms, wherein R6 represents another chain of the crosslinked polymer particle comprised of structures represented by Formulas (I), (II), and (III), wherein x, y, and z represent an integer from 1 to 100, wherein n represents an integer 1 to 10,000, wherein A1 is an oxygen atom or a secondary amine, where A2 is an oxygen atom or a secondary amine the polymeric particles including a drug in the particles and the structure of Formula III being hydrolysable to permit the release of the drug from the particles, the polymeric particles when made from a free radical dispersion polymerization at 25° C. having a higher drug-loading capacity than a drug-loading capacity of polymeric particles made from the same monomers which are polymerized at above about 60° C. ### Claim 18 (depends on 17) The blend of polymeric particles of claim 17, wherein R1-R5 each represent a methyl group. ### Claim 19 (depends on 17) The blend of polymeric particles of claim 17, wherein a ratio of the structure represented by Formula (I) to Formula (II) is from about 12:1 to about 6:4. ### Claim 20 (depends on 17) The blend of polymeric particles of claim 17, wherein the amount of Formula (I) relative to the amount of sum of Formulas (I) and (II) is from about 1 mol % to about 4 mol % based on the total amount of copolymer. ### Claim 21 (depends on 17) The blend of polymeric particles of claim 17, wherein the average size of the polymeric particles is from about to 50 nm to about 431.6 nm. ### Claim 22 (depends on 17) The polymer particle of claim 17 wherein the drug is selected from the group consisting of 2-chloro-3-diacetylamino-1,4-naphthoquinone, docetaxel, doxorubicin, and paclitaxel. ### Claim 23 (depends on 1) The blend of polymeric particles of claim 1 wherein the polymeric particles when made from a free radical dispersion polymerization at 25° C. have a higher drug-loading capacity than a drug-loading capacity of polymeric particles polymerized from the same monomers polymerized at 60° C. or above. ### Claim 24 (depends on 9) The blend of polymeric particles of claim 9 wherein the polymeric particles when made from a free radical dispersion polymerization at 25° C. have a higher drug-loading capacity than a drug-loading capacity of polymeric particles polymerized from the same monomers polymerized at 60° C. or above. ### Claim 25 (depends on 24) The blend of polymers particles of claim 24 wherein the particle releases a drug with less burst than polymer particle made from the same monomers polymerized by an emulsion polymerization reaction. ### Claim 26 (depends on 3) The blend of polymeric particles of claim 3, wherein the hydrolysable crosslinker is selected from the group consisting of N,O-dimethacryloylhydroxylamine, di(2-acryloyloxy ethoxy)-[4-hydroxyphenyl]methane, ethylene glycol dimethacrylate, 4,4′-di(methacryloylamino)azobenzene, N,N′-methylenebisacrylamide, tetraethylene glycol dimethacrylate, ethylene glycol divinyl carbonate, and methacryloxyethyl vinyl carbonate. ### Claim 27 (depends on 9) The blend of polymeric particles of claim 9, wherein the hydrolysable crosslinker is selected from the group consisting of N,O-dimethacryloylhydroxylamine, di(2-acryloyloxy ethoxy)-[4-hydroxyphenyl]methane, ethylene glycol dimethacrylate, 4,4′-di(methacryloylamino)azobenzene, N,N′-methylenebisacrylamide, tetraethylene glycol dimethacrylate, ethylene glycol divinyl carbonate, and methacryloxyethyl vinyl carbonate. ### Claim 28 (depends on 9) The blend of polymeric particles of claim 9, wherein the therapeutic agent is selected from the group consisting of 2-chloro-3-diacetylamino-1,4-naphthoquinone, docetaxel, doxorubicin and paclitaxel.