Biodegradable triblock copolymers for implantable devices

• US 20090004243A1
• Filed: 06/29/2007
• Published: 01/01/2009
• Est. Priority Date: 06/29/2007
• Status: Abandoned Application

• Current Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: Abbott Cardiovascular Systems Incorporated (Abbott Laboratories Incorporated)
• Inventors: Trollsas, Mikael, Pacetti, Stephen D.
• Application Number:
  US11/824,011
• Publication Number:
  US 20090004243A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2420/00 Materials or methods for coatings medical devices
• CPC Class Codes: A61L 29/041 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42

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.

Claims

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

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.