US2013129830A1PendingUtilityA1

Polymer Protein Microparticles

Assignee: REGENERON PHARMAPriority: Nov 18, 2011Filed: Nov 18, 2012Published: May 23, 2013
Est. expiryNov 18, 2031(~5.3 yrs left)· nominal 20-yr term from priority
A61K 9/1647A61P 27/02A61K 9/1641A61K 9/1623A61K 9/5031A61K 9/1617A61K 9/1611A61K 9/5047A61K 38/179A61K 9/14A61K 9/1652A61K 9/5089A61K 38/00A61K 47/36A61K 2039/505A61K 47/34
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Claims

Abstract

Microparticles containing a core of therapeutic protein and a cortex of a biocompatible and biodegradable polymer, and methods of making and using the microparticles are provided. The extended release of a therapeutic protein from the microparticles in a physiological solution is demonstrated over an extended period of time.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A composition comprising a protein coated with a polymer, wherein the composition is a particle with a diameter of from about 5 μm to about 40 μm. 
     
     
         2 . The composition of  claim 1 , wherein the protein is an antigen-binding protein. 
     
     
         3 . The composition of  claim 2 , wherein the protein comprises an Fc domain. 
     
     
         4 . The composition of  claim 3 , wherein the protein is an antibody. 
     
     
         5 . The composition of  claim 3 , wherein the protein is a receptor-Fc-fusion protein. 
     
     
         6 . The composition of  claim 2 , wherein the protein is an antibody fragment. 
     
     
         7 . The composition of  claim 5 , wherein the protein is a VEGF-Trap. 
     
     
         8 . The composition of  claim 4 , wherein the antibody is a human monoclonal antibody. 
     
     
         9 . The composition of  claim 1 , wherein the polymer is a biodegradable polymer. 
     
     
         10 . The composition of  claim 9 , wherein the polymer is selected from the group consisting of poly (lactic acid) (PLA), polyanhydride poly[1,6-bis(p-carboxyphenoxy)hexane] (pCPH), poly(hydroxbutyric acid-cohydroxyvaleric acid) (PHB-PVA), polyethylene glycol-poly (lactic acid) copolymer (PEG-PLA), poly- D,L -lactide-co-glycolide (PLGA), polyorthoester (POE), ethyl cellulose (EC), and poly-ε-caprolactone (PCL). 
     
     
         11 . The composition of  claim 1 , wherein the protein is either a trap or an antibody, and the polymer is a POE. 
     
     
         12 . The composition of  claim 11 , wherein the average diameter of the particle is about 15 μm. 
     
     
         13 . The composition of  claim 1 , wherein the protein is either a trap or an antibody, and the polymer is a PLGA. 
     
     
         14 . A microparticle having a diameter of about 2 μm to about 70 μm comprising a protein particle core of about 2 μm to about 12 μm in diameter and a biodegradable polymer cortex. 
     
     
         15 . The microparticle of  claim 14 , wherein the biodegradable polymer is selected from the group consisting of poly (lactic acid) (PLA), polyanhydride poly[1,6-bis(p-carboxyphenoxy)hexane] (pCPH), poly(hydroxbutyric acid-cohydroxyvaleric acid) (PHB-PVA), polyethylene glycol-poly (lactic acid) copolymer (PEG-PLA), poly- D,L -lactide-co-glycolide (PLGA), polyorthoester (POE), ethyl cellulose (EC), and poly-ε-caprolactone (PCL). 
     
     
         16 . The microparticle of  claim 15 , wherein the protein particle core comprises an antigen-binding protein. 
     
     
         17 . The microparticle of  claim 16 , wherein the antigen binding protein is a receptor-Fc-fusion protein. 
     
     
         18 . The microparticle of  claim 17 , wherein the protein particle core comprises a VEGF-Trap and the polymer cortex comprises POE, PLA, or PLGA. 
     
     
         19 . The microparticle of  claim 16 , wherein the antigen binding protein is an antibody. 
     
     
         20 . The microparticle of  claim 19 , wherein the antibody is a human IgG molecule, and the polymer cortex comprises POE, PLA, or PLGA. 
     
     
         21 . A plurality of microparticles having diameters ranging from about 2 μm to about 70 μm comprising a protein particle core of about 2 μm to about 12 μm in diameter and a biodegradable polymer cortex. 
     
     
         22 . The plurality of microparticles of  claim 21 , wherein the microparticles degrade at different rates and the protein is released in an aqueous environment over an extended period of time. 
     
     
         23 . The plurality of microparticles of  claim 22 , wherein the period of time is at least 3 days. 
     
     
         24 . The plurality of microparticles of  claim 23 , wherein the period of time is at least 60 days. 
     
     
         25 . The plurality of microparticles of  claim 24 , wherein the protein is an antigen-binding protein. 
     
     
         26 . The plurality of microparticles of  claim 25 , wherein the antigen-binding protein is a receptor-Fc-fusion protein. 
     
     
         27 . The plurality of microparticles of  claim 26 , wherein the receptor-Fc-fusion protein is a VEGF Trap and the polymer cortex comprises POE, PLA, or PLGA. 
     
     
         28 . The plurality of microparticles of  claim 25 , wherein the antigen-binding protein is an antibody. 
     
     
         29 . The plurality of microparticles of  claim 28 , wherein the antibody is a human IgG molecule and the polymer cortex comprises POE, PLA, or PLGA. 
     
     
         30 . A method of treating a disease, comprising administering to a patient a therapeutically effective amount of a plurality of microparticles of  claim 21 , wherein a therapeutic protein is released from the microparticles over an extended period of time. 
     
     
         31 . The method of  claim 30 , wherein the protein is a VEGF-Trap and the polymer is POE, PLA, or PLGA. 
     
     
         32 . The method of  claim 31 , wherein the disease is an ocular disease and the microparticles are delivered to the vitreous of the patient at no less than 60 day intervals. 
     
     
         33 . A method of manufacturing a composition comprising a protein and a biodegradable polymer, the method comprising the steps of:
 a. obtaining a protein particle;   b. suspending the protein particle in a solution comprising the polymer and a solvent; and   c. removing the solvent,   
       wherein a particle is formed comprising the protein coated with the polymer. 
     
     
         34 . The method of  claim 33 , wherein the protein particle is obtained by spray drying a solution comprising the protein. 
     
     
         35 . The method of  claim 34 , wherein the spray drying is performed by dual-nozzle sonication, single-nozzle sonication, or electrospray. 
     
     
         36 . The method of  claim 35 , wherein the solvent is evaporated by creating a dispersion of the protein suspension of step (b) by spray drying. 
     
     
         37 . The method of  claim 36 , wherein the solvent is removed by heat evaporation, air evaporation, or extraction. 
     
     
         38 . The method of  claim 37 , wherein the polymer is selected from the group consisting of poly (lactic acid) (PLA), polyanhydride poly[1,6-bis(p-carboxyphenoxy)hexane] (pCPH), poly(hydroxbutyric acid-cohydroxyvaleric acid) (PHB-PVA), polyethylene glycol-poly (lactic acid) copolymer (PEG-PLA), poly- D,L -lactide-co-glycolide (PLGA), polyorthoester (POE), ethyl cellulose (EC), and poly-ε-caprolactone (PCL). 
     
     
         39 . The method of  claim 38 , wherein the protein is a receptor-Fc-fusion protein or an antibody. 
     
     
         40 . The method of  claim 39 , wherein the protein is a VEGF-Trap or an IgG molecule, and the polymer is POE, PLA, or PLGA. 
     
     
         41 . The method of  claim 40 , wherein the particle has an average diameter of about 15 μm. 
     
     
         42 . A method for modulating the release of a protein, comprising the step of (a) combining a protein with a biodegradable polymer to form a protein-polymer complex; followed by the step of (b) contacting the protein-polymer complex with a solvent, wherein the polymer degrades over time and the protein is gradually released into the solvent. 
     
     
         43 . The method of  claim 42 , wherein step (a) is performed according to  claim 39 . 
     
     
         44 . The method of  claim 43 , wherein the protein is a VEGF-Trap or an IgG molecule, and the polymer is POE, PLA, or PLGA. 
     
     
         45 . The method of  claim 44 , wherein the particle has an average diameter of about 15 μm. 
     
     
         46 . The method of  claim 45 , wherein the protein is released from the protein-polymer complex over at least three days. 
     
     
         47 . The method of  claim 45 , wherein the protein is released from the protein-polymer complex over at least 60 days. 
     
     
         48 . The method of  claim 47 , wherein the solvent is buffered saline. 
     
     
         49 . The method of  claim 47 , wherein the solvent is in vivo. 
     
     
         50 . The method of  claim 49 , wherein the solvent is vitreous humour.

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