Dioxanone-based copolymers for implantable devices

Abstract

The present invention is directed to polymeric materials comprising biodegradable, dioxanone-based copolymers and implantable devices (e.g., drug-delivery stents) formed of such materials. The polymeric materials can also contain at least one additional biocompatible moiety, at least one non-fouling moiety, at least one biobeneficial material, at least one bioactive agent, or a combination thereof. The polymeric materials are designed to improve the mechanical, physical and biological properties of implantable devices formed thereof.

1 . A composition comprising a biodegradable copolymer, wherein the copolymer:
 is derived from dioxanone and at least one additional ester-, carbonate- or ether-based monomer;   has a crystallinity of about 80% or less;   has a T g  from about −100° C. to about 100° C.;   has a polymer number-average molecular weight (M n ) from about 10 kDa to about 1,500 kDa; and   completely or substantially completely degrades within about 24 months.   
     
     
         2 . The composition of  claim 1 , wherein the copolymer:
 has a crystallinity from about 5% to about 70%;   has a T g  from about −60° C. to about 60° C.;   has an M n  from about 20 kDa to about 1,000 kDa; and   completely or substantially completely degrades within about 12 months.   
     
     
         3 . The composition of  claim 2 , wherein the copolymer:
 has a crystallinity from about 10% to about 60%;   has a T g  from about −30° C. to about 30° C.;   has an M n  from about 30 kDa to about 700 kDa; and   completely or substantially completely degrades within about 6 months.   
     
     
         4 . The composition of  claim 1 , wherein the copolymer is derived from dioxanone and one to five additional ester-based monomers, carbonate-based monomers, ether-based monomers, or a combination thereof. 
     
     
         5 . The composition of  claim 1 , wherein dioxanone and the at least one additional ester-, carbonate- or ether-based monomer each independently have from about 5 to about 5,000 monomer units. 
     
     
         6 . The composition of  claim 1 , wherein the at least one additional ester-, carbonate- or ether-based monomer is selected from glycolide (GA), D-lactide (DLA), L-lactide (LLA), D,L-lactide (DLLA), C 3 -C 12  β-lactone, C 4 -C 12  γ-lactone, α-bromo-γ-butyrolactone, α-bromo-γ-valerolactone, homoserine lactone C 2 -C 14  amide, C 5 -C 14  δ-lactone, mevalonolactone, C 6 -C 16  ε-lactone, 1,3-dioxolan-2-one, 4-methyl-1,3-dioxolan-2-one, 4-methoxymethyl-1,3-dioxolan-2-one, 4-chloro-1,3-dioxolan-2-one, 4-phenyl-1,3-dioxolan-2-one, 4-vinyl-1,3-dioxolan-2-one, trimethylene carbonate (TMC), ethylene oxide (EO), and propylene oxide (PPO). 
     
     
         7 . The composition of  claim 6 , wherein the at least one additional ester-, carbonate- or ether-based monomer is selected from GA, DLA, LLA, DLLA, β-propiolactone (PL), β-butyrolactone (BL), δ-valerolactone (VL), ε-caprolactone (CL), TMC, EO, and PPO. 
     
     
         8 . The composition of  claim 7 , wherein the copolymer is derived from dioxanone (DS) and one to three additional ester-based monomers, carbonate-based monomers, ether-based monomers or a combination thereof, and wherein the individual units of each different type of monomer can be arranged in any manner. 
     
     
         9 . The composition of  claim 8 , wherein the copolymer is selected from P(DS-GA), P(DS-DLA), P(DS-LLA), P(DS-DLLA), P(DS-PL), P(DS-BL), P(DS-VL), P(DS-CL), P(DS-TMC), P(DS-EO), P(DS-PPO), P(DS-GA-DLA), P(DS-GA-LLA), P(DS-GA-DLLA), P(DS-GA-VL), P(DS-GA-CL), P(DS-GA-TMC), P(DS-GA-EO), P(DS-GA-PPO), P(DS-DLA-LLA), P(DS-DLA-DLLA), P(DS-DLA-VL), P(DS-DLA-CL), P(DS-DLA-TMC), P(DS-DLA-EO), P(DS-DLA-PPO), P(DS-LLA-DLLA), P(DS-LLA-VL), P(DS-LLA-CL), P(DS-LLA-TMC), P(DS-LLA-EO), P(DS-LLA-PPO), P(DS-DLLA-VL), P(DS-DLLA-CL), P(DS-DLLA-TMC), P(DS-DLLA-EO), P(DS-DLLA-PPO), P(DS-VL-CL), P(DS-VL-TMC), P(DS-VL-EO), P(DS-VL-PPO), P(DS-CL-TMC), P(DS-CL-EO), P(DS-CL-PPO), P(DS-GA-DLLA-CL), P(DS-GA-DLLA-TMC), P(DS-GA-DLLA-EO), P(DS-GA-CL-TMC), P(DS-GA-CL-EO), P(DS-GA-TMC-EO), P(DS-DLLA-CL-TMC), P(DS-DLLA-CL-EO), P(DS-DLLA-TMC-EO), and P(DS-CL-TMC-EO). 
     
     
         10 . The composition of  claim 1 , further comprising at least one additional biocompatible moiety. 
     
     
         11 . The composition of  claim 10 , wherein the at least one additional biocompatible moiety is selected from poly(ethylene oxide), polypropylene glycol), poly(tetramethylene glycol), poly(ethylene oxide-co-propylene oxide), ε-caprolactone, β-butyrolactone, δ-valerolactone, glycolide, poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid) and salts thereof, poly(styrene sulfonate), sulfonated dextran, polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate), sialic acid, hyaluronic acid and derivatives thereof, copolymers of poly(ethylene glycol) (PEG) with hyaluronic acid or derivatives thereof, heparin, copolymers of PEG with heparin, graft copolymers of poly(L-lysine) and PEG, and copolymers thereof. 
     
     
         12 . The composition of  claim 1 , further comprising at least one non-fouling moiety. 
     
     
         13 . The composition of  claim 12 , wherein the at least one non-fouling moiety is selected from polyethylene glycol, polypropylene glycol, Pluronic™ surfactants, poly(2-hydroxyethyl methacrylate), poly(vinyl alcohol), polyalkene oxides, poly(n-propylmethacrylamide), poly(N-vinyl-2-pyrrolidone), sulfonated polystyrene, dextran, sulfonated dextran, dextrin, hyaluronic acid, sodium hyaluronate, and derivatives thereof. 
     
     
         14 . The composition of  claim 1 , further comprising at least one biobeneficial material. 
     
     
         15 . The composition of  claim 14 , wherein the at least one biobeneficial material is selected from fibrin, fibrinogen, cellulose and derivatives thereof, starch, pectin, chitosan, elastin, gelatin, alginate and conjugates thereof, collagen and conjugates thereof, hyaluronan and derivatives thereof, hyaluronic acid, sodium hyaluronate, and self-assembled peptides. 
     
     
         16 . The composition of  claim 1 , further comprising at least one biologically active agent selected from antiproliferative, antineoplastic, antimitotic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic, antiallergic and antioxidant substances. 
     
     
         17 . The composition of  claim 16 , wherein the at least one biologically active agent is selected from paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxyl)ethyl-rapamycin (everolimus), 40-O-(2-ethoxyl)ethyl-rapamycin (biolimus), 40-O-(3-hydroxyl)propyl-rapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinib mesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies, prohealing drugs, prodrugs thereof, co-drugs thereof, and a combination thereof. 
     
     
         18 . A coating comprising the composition of  claim 1 . 
     
     
         19 . The coating of  claim 18 , which has a thickness of ≦about 10 micron and completely or substantially completely degrades within about 12 months. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . An implantable device formed of a material comprising the composition of  claim 1 . 
     
     
         25 . The device of  claim 24 , wherein the material is a coating disposed over at least a portion of the device. 
     
     
         26 . The device of  claim 25 , wherein the coating has a thickness of ≦about 10 micron and completely or substantially completely degrades within about 12 months. 
     
     
         27 . The device of  claim 24 , which is selected from stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, valves, and particles. 
     
     
         28 . The device of  claim 27 , which is a stent. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . A method of preparing the composition of  claim 1 , comprising performing ring-opening polymerization (ROP) reactions with an initiator, dioxanone and at least one additional ester-, carbonate- or ether-based monomer, wherein:
 the initiator has one or two active hydroxyl, amino or thiol end groups.   
     
     
         35 . A method of fabricating an implantable device, comprising forming the device of a material comprising the composition of  claim 1 . 
     
     
         36 . The method of  claim 35 , comprising depositing the material as a coating over at least a portion of the implantable device. 
     
     
         37 . A method of treating or preventing a condition or disorder in a patient, comprising implanting in the patient an implantable device formed of a material comprising the composition of  claim 1 , wherein the condition or disorder is selected from atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection, vascular perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, patent foramen ovale, claudication, anastomotic proliferation of vein and artificial grafts, arteriovenous anastamoses, bile duct obstruction, ureter obstruction and tumor obstruction. 
     
     
         38 . The method of  claim 37 , wherein the composition further comprises at least one additional biocompatible moiety. 
     
     
         39 . The method of  claim 37 , wherein the composition further comprises at least one non-fouling moiety. 
     
     
         40 . The method of  claim 37 , wherein the composition further comprises at least one biobeneficial material. 
     
     
         41 . The method of  claim 37 , wherein the composition further comprises at least one biologically active agent selected from antiproliferative, antineoplastic, antimitotic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic, antiallergic and antioxidant substances. 
     
     
         42 . The method of  claim 41 , wherein the at least one biologically active agent is selected from paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide dismutases, super oxide dismutase mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, 40-O-(2-hydroxyl)ethyl-rapamycin (everolimus), 40-O-(2-ethoxyl)ethyl-rapamycin (biolimus), 40-O-(3-hydroxyl)propyl-rapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin (zotarolimus), pimecrolimus, imatinib mesylate, midostaurin, clobetasol, progenitor cell-capturing antibodies, prohealing drugs, prodrugs thereof, co-drugs thereof, and a combination thereof. 
     
     
         43 . The method of  claim 37 , wherein the material is a coating disposed over at least a portion of the implantable device. 
     
     
         44 . The method of  claim 37 , wherein the implantable device is selected from stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, valves, and particles. 
     
     
         45 . The method of  claim 44 , wherein the implantable device is a stent.