Biodegradable triblock copolymers for implantable devices

Abstract

The present invention is directed to polymeric materials made of biodegradable, bioabsorbable triblock copolymers and implantable devices (e.g., drug-delivery stents) containing such polymeric materials. The polymeric materials may also contain at least one therapeutic substance. The polymeric materials are formulated so as to improve the mechanical and adhesion properties, degradation, biocompatibility and drug permeability of such materials and, thus, implantable devices formed of such materials.

1 . A composition comprising a biodegradable triblock copolymer of the structure A-B-A′, wherein:
 the A and A′ blocks each independently are hard blocks having a T g  or T m  above body temperature;   the B block is a soft block having a T g  less than the T g  or T m  of the A and A′ blocks;   the A, B and A′ blocks each independently have a polymer number-average molecular weight (M n ) from about 1 kDa to about 500 kDa; and   the A and A′ blocks may be the same or different.   
     
     
         2 . The composition of  claim 1 , wherein the tensile modulus of the hard A and A′ blocks independently is greater than about 1,000 MPa, and the tensile modulus of the soft B block is less than about 1,000 MPa. 
     
     
         3 . The composition of  claim 1 , wherein the weight fraction of the A and A′ blocks is from about 1% to about 99% of the triblock copolymer. 
     
     
         4 . The composition of  claim 1 , wherein the A, B and A′ blocks each independently comprise a polymer comprising from one to four different types of monomer, wherein each type of monomer has from about 5 to about 5,000 monomer units. 
     
     
         5 . The composition of  claim 1 , wherein the A and A′ blocks are the same. 
     
     
         6 . The composition of  claim 1 , wherein the A and A′ blocks are different. 
     
     
         7 . The composition of  claim 1 , wherein:
 the A and A′ blocks each independently comprise a polymer selected from the group consisting of poly(L-lactide) (PLLA), poly(D,L-lactide), poly(glycolide) (PGA), poly(GA-co-D,L-lactide), poly(GA-co-L-lactide), and any variations in the arrangement of the monomers thereof; and   the B block comprises a polymer selected from the group consisting of poly(caprolactone) (PCL), poly(CL-co-GA), poly(trimethylene carbonate) (PTMC), poly(TMC-co-GA), poly(TMC-co-D,L-lactide), poly(TMC-co-L-lactide), poly(TMC-co-CL), poly(TMC-co-D,L-lactide-co-GA), poly(TMC-co-CL-co-GA), poly(dioxanone), poly(TMC-co-dioxanone), poly(dioxanone-co-CL), poly(dioxanone-co-D,L-lactide), poly(dioxanone-co-L-lactide), poly(dioxanone-co-GA), poly(dioxanone-co-D,L-lactide-co-GA), polyketals, and any variations in the arrangement of the monomers thereof.   
     
     
         8 . The composition of  claim 7 , wherein the polyketal polymer of the B block has the structure of 
       
         
           
           
               
               
           
         
       
       wherein R 1  is a poly(caprolactone) diol or a C 2 -C 24  diol of the structure, HO—R 1 —OH, that contains an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, or a combination thereof, and n is an integer from about 5 to about 5,000. 
     
     
         9 . The composition of  claim 1 , wherein the B block is immiscible with the A and A′ blocks. 
     
     
         10 . The composition of  claim 1 , further comprising at least one dihydroxyaryl group conjugated to the polymer ends of the triblock copolymer. 
     
     
         11 . The composition of  claim 10 , wherein the at least one dihydroxyaryl group contains a 3,4-dihydroxyphenyl moiety. 
     
     
         12 . The composition of  claim 1 , further comprising at least one biocompatible moiety. 
     
     
         13 . The composition of  claim 12 , wherein the at least one biocompatible moiety is selected from the group consisting of poly(ethylene oxide), poly(propylene glycol), poly(tetramethylene glycol), polyethylene 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 or derivatives thereof, copolymers of poly(ethylene glycol) with hyaluronic acid or derivatives thereof, heparin, copolymers of polyethylene glycol with heparin, a graft copolymer of poly(L-lysine) and poly(ethylene glycol), and copolymers thereof. 
     
     
         14 . The composition of  claim 1 , further comprising at least one additional biologically absorbable polymer. 
     
     
         15 . The composition of  claim 14 , wherein the at least one additional biologically absorbable polymer is selected from the group consisting of poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-co-valerate), poly(caprolactone), poly(lactide-co-glycolide), poly(ethylene-glycol)-block-poly(butyleneterephthalate), poly(ethylene-glycol)-block-poly(butylene terephthalate)-block-polyethylene-glycol), poly(butyleneterephthalate)-block-poly(ethylene-glycol)-block poly(butyleneterephthalate), poly(ethylene-glycol)-block-poly(caprolactone), poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol), poly(caprolactone)-block-poly(ethylene-glycol)-block-poly(caprolactone), and blends thereof. 
     
     
         16 . The composition of  claim 1 , further comprising at least one biologically active agent selected from the group consisting of 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 the group consisting of 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-hydroxy)ethyl-rapamycin (everolimus), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 40-epi-(N-1-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 loses about 100% of its mass within about 12 months. 
     
     
         20 . A coating comprising the composition of  claim 10 . 
     
     
         21 . A coating comprising the composition of  claim 12 . 
     
     
         22 . A coating comprising the composition of  claim 14 . 
     
     
         23 . A coating comprising the composition of  claim 16 . 
     
     
         24 . The coating of  claim 23 , which has a thickness of ≦about 10 micron and loses about 100% of its mass within about 12 months. 
     
     
         25 . A coating comprising the composition of  claim 17 . 
     
     
         26 . An implantable device formed of a material comprising the composition of  claim 1 . 
     
     
         27 . The device of  claim 26 , wherein the material is a coating disposed over the device. 
     
     
         28 . The device of  claim 27 , wherein the coating has a thickness of ≦about 10 micron and loses about 100% of its mass within about 12 months. 
     
     
         29 . The device of  claim 26 , which is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves. 
     
     
         30 . An implantable device formed of a material comprising the composition of  claim 10 . 
     
     
         31 . An implantable device formed of a material comprising the composition of  claim 12 . 
     
     
         32 . An implantable device formed of a material comprising the composition of  claim 14 . 
     
     
         33 . An implantable device formed of a material comprising the composition of  claim 16 . 
     
     
         34 . The device of  claim 33 , wherein the material is a coating disposed over the device. 
     
     
         35 . The device of  claim 34 , wherein the coating has a thickness of ≦about 10 micron and loses about 100% of its mass within about 12 months. 
     
     
         36 . The device of  claim 33 , which is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves. 
     
     
         37 . The device of  claim 36 , which is a stent. 
     
     
         38 . An implantable device formed of a material comprising the composition of  claim 17 . 
     
     
         39 . A method of preparing the composition of  claim 5 , comprising:
 performing ring-opening polymerization (ROP) with the corresponding monomer(s) of the B block, wherein an initiating compound containing two active end groups is used to initiate ROP with the first monomer of the B block, and wherein the two active end groups on the initiating compound are independently a hydroxyl, amino or thiol group; and   performing ROP with the corresponding monomer(s) of the A and A′ blocks.   
     
     
         40 . A method of preparing the composition of  claim 6 , comprising:
 performing ring-opening polymerization (ROP) with the corresponding monomer(s) of the B block, wherein an initiating compound containing one active end group and one protected end group is used to initiate ROP with the first monomer of the B block, and wherein the active end group on the initiating compound is a hydroxyl, amino or thiol group, and the protected end group on the initiating compound is a protected hydroxyl, amino or thiol group;   performing ROP with the corresponding monomer(s) of the A block;   protecting any active group formed at the polymer end of the A block;   deprotecting the protected end group derived from the initiating compound at the polymer end of the B block;   performing ROP with the corresponding monomer(s) of the A′ blocks; and   optionally deprotecting the protected active group at the polymer end of the A block.   
     
     
         41 . A method of fabricating an implantable device, comprising forming the device of a material comprising the composition of  claim 1 . 
     
     
         42 . The method of  claim 41 , comprising depositing the material as a coating over at least a portion of the implantable device. 
     
     
         43 . The method of  claim 41 , wherein the implantable device is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves. 
     
     
         44 . A method of fabricating an implantable device, comprising forming the device of a material comprising the composition of  claim 16 . 
     
     
         45 . The method of  claim 44 , comprising depositing the material as a coating over at least a portion of the implantable device. 
     
     
         46 . The method of  claim 44 , wherein the implantable device is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves. 
     
     
         47 . A method of treating or preventing a condition or disorder in a patient, comprising implanting in the patient the implantable device of  claim 26 , wherein the condition or disorder is selected from the group consisting of 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, bile duct obstruction, ureter obstruction and tumor obstruction. 
     
     
         48 . The method of  claim 47 , wherein the implantable device is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves. 
     
     
         49 . A method of treating or preventing a condition or disorder in a patient, comprising implanting in the patient the implantable device of  claim 33 , wherein the condition or disorder is selected from the group consisting of 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, bile duct obstruction, ureter obstruction and tumor obstruction. 
     
     
         50 . The method of  claim 49 , wherein the implantable device is selected from the group consisting of stents, grafts, stent-grafts, catheters, leads and electrodes, clips, shunts, closure devices, and valves.