Microparticles For The Treatment Of Disease

Abstract

Microparticle-bioactive agent based treatments for local treatment of diseased tissues/organs are disclosed.

What is claimed is: 
     
         1 . A drug delivery system, comprising:
 a plurality of narrow polydispersity microparticles, wherein   the microparticles comprise a polymer selected from the group consisting of poly(lactide-co-glycolide-co-caprolactone), poly(lactide-bl-glycolide), poly(lactide-co-glycolide)-bl-polyethyleneglycol, poly(lactide-co-glycolide)-bl-polyethylene glycol-bl-poly(lactide-co-glycolide), poly(lactide-co-glycolide-co-caprolactone), poly(lactide-co-glycolide-co-hydroxybutyric acid), poly(lactide-co-glycolide-co-trimethylene carbonate), poly(lactide-co-glycolide)-bl-polycaprolactone, poly(lactide-co-glycolide)-bl-poly(hydroxybutyric acid), poly(lactide-co-glycolide)-bl-poly(methylene carbonate) and blends of two or more of the preceding; and,   a bioactive agent adhered to surfaces of, incorporated into or integrated into the structure of the microparticles.   
     
     
         2 . The drug delivery system of  claim 1 , wherein the lactide is selected from the group consisting of l-lactide, d-lactide, d,l-lactide or meso-lactide. 
     
     
         3 . The drug delivery system of  claim 1 , wherein the microparticles have a mean particle size of about 8 to about 20 microns. 
     
     
         4 . The drug delivery system of  claim 3 , wherein the microparticles have a mean particle size of about 10 to about 15 microns. 
     
     
         5 . The drug delivery system of  claim 3 , wherein the microparticles are substantially spherical and the mean particle size is a mean diameter. 
     
     
         6 . The drug delivery system according to  claim 1 , wherein the mole percent of caprolactone in the poly(lactide-co-glycolide-co-caprolactone) is about 10% to about 70%. 
     
     
         7 . The drug delivery system according to  claim 6 , wherein the mole percent of caprolactone in the poly(lactide-co-glycolide-co-caprolactone) is less than about 50%. 
     
     
         8 . The drug delivery system according to  claim 1 , wherein the mole percent of glycolide in the poly(lactide-co-glycolide-co-caprolactone) is about 10% to about 50%. 
     
     
         9 . The drug delivery system according to  claim 8 , wherein the mole percent of glycolide in the poly(lactide-co-glycolide-co-caprolactone) is less than 50%. 
     
     
         10 . The drug delivery system according to  claim 1 , wherein the mole percent of lactide in the poly(lactide-co-glycolide-co-caprolactone) is more than about 50%. 
     
     
         11 . The drug delivery system according to  claim 1 , wherein the mole percent of glycolide in the poly(lactide-co-glycolide)-bl-polyethylene glycol is about 10-50%. 
     
     
         12 . The drug delivery system according to  claim 11 , wherein the mole percent of glycolide in the poly(lactide-co-glycolide)-bl-polyethylene glycol is less than 50%. 
     
     
         13 . The drug delivery system according to  claim 1 , wherein the mole percent of polyethylene glycol in the poly(lactide-co-glycolide)-bl-polyethylene glycol is about 1-50%. 
     
     
         14 . The drug delivery system according to  claim 1 , wherein the mole percent of lactide in the poly(lactide-glycolide)-bl-polyethylene glycol is about 50% to about 90%. 
     
     
         15 . The drug delivery system according to  claim 1 , wherein the bioactive agent is selected from the group consisting of a TGF-β pathway inhibitor, a protein kinase C pathway inhibitor, a CTGF pathway inhibitor, an mTOR pathway inhibitor, an antibody against TGF-β, an antibody against CTGF, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, a calcium channel blocker, a vasodilator, a direct renin inhibitor, erythropoietin, an inhibitor of AGE-RAGE signaling, an inhibitor of SMAD signaling, iron and immuno-suppressives. 
     
     
         16 . The drug delivery system according to  claim 15 , wherein the TGF-β pathway inhibitor is halofuginone. 
     
     
         17 . The drug delivery system according to  claim 15 , wherein the protein kinase C pathway inhibitor is reboxistaurin. 
     
     
         18 . The drug delivery system according to  claim 15 , wherein the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, zotarolimus, pimecrolimus, temsirolimus and biolimus. 
     
     
         19 . A method of treating a disease comprising administering the drug delivery system of  claim 1  into the artery of a patient in need thereof, wherein:
 less than 10% of the microparticles degrade under physiological conditions to release a therapeutic amount of the bioactive agent within 1 week of administration and more than 90% of the microparticles degrade under physiological conditions to release a therapeutic amount of the bioactive agent within 12 months of administration. 
 
     
     
         20 . The method according to  claim 19 , wherein the microparticles have a mean diameter such that at least 80% of them are trapped in glomeruli of the kidney on a first pass. 
     
     
         21 . The method of  claim 20 , wherein at least 90% of the microparticles are trapped in the glomeruli of the kidney on the first pass. 
     
     
         22 . The method of  claim 21 , wherein at least 99% of the microparticles are trapped in the glomeruli of the kidney on the first pass. 
     
     
         23 . The method according to  claim 19 , wherein the disease is a kidney disease selected from a group consisting of chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA Nephritis, lupus nephritis, reflux nephropathy, glomerulonephritis, glomerulonephrosis and polycystic renal disease. 
     
     
         24 . A method comprising:
 dissolving a polymer and a hydrophobic bioactive agent in a water immiscible solvent mixture comprising at least one solvent with a boiling point less than about 60° C. and at least one solvent with a boiling point more than about 60° C. to make an organic phase solution;   adding the organic phase solution under high shear to an aqueous phase and sonicating to form an emulsion;   passing the emulsion through a porous membrane of a selected pore size;   removing the organic solvents; and   creating a release rate curve for the bioactive agent from the resulting microparticles.   
     
     
         25 . The method according to  claim 24 , wherein if a slower release rate is desired, the relative amount of the solvent with a boiling point more than about 60° C. is decreased within the solvent mixture. 
     
     
         26 . The method according to  claim 24 , wherein if a faster release rate is desired, the relative amount of the solvent with a boiling point more than about 60° C. is increased within the solvent mixture. 
     
     
         27 . The method according to  claim 24 , wherein the solvent with a boiling point less than about 60° C. comprises dichloromethane or chloroform. 
     
     
         28 . The method according to  claim 24 , wherein the solvent with a boiling point more than about 60° C. comprises ethyl acetate, methyl ethyl ketone or methyl isobutyl ketone. 
     
     
         29 . The method according to  claim 24 , wherein the solvent mixture comprises 90/10 dichloromethane/ethyl acetate. 
     
     
         30 . The method according to  claim 24 , wherein the solvent mixture comprises 80/20 dichloromethane/ethyl acetate. 
     
     
         31 . The method according to  claim 24 , wherein the bioactive agent is selected from the group consisting of a TGF-β pathway inhibitor, a protein kinase C pathway inhibitor, a CTGF pathway inhibitor, an mTOR pathway inhibitor, an antibody against TGF-β, an antibody against CTGF, an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, a calcium channel blocker, a vasodilator, a direct renin inhibitor, erythropoietin, an inhibitor of AGE-RAGE signaling, an inhibitor of SMAD signaling, iron and immunosuppresives. 
     
     
         32 . The method according to  claim 31 , wherein the TGF-β pathway inhibitor is halofuginone. 
     
     
         33 . The method according to  claim 31 , wherein the protein kinase C pathway inhibitor is reboxistaurin. 
     
     
         34 . The method according to  claim 31 , wherein the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, zotarolimus, pimecrolimus, temsirolimus and biolimus.