Methods for modulating thermal and mechanical properties of coatings on implantable devices

• US 20050245637A1
• Filed: 04/30/2004
• Published: 11/03/2005
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: DesNoyer, Jessica Renee, Borgankow, Harshad, Tang, Yiwen, Pacetti, Stephen D., Hossainy, Syed Faiyaz Ahmed
• Granted Patent: US 7,820,732 B2
• Time in Patent Office: Days
• US Class Current: 523/113
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• 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

Abstract

Methods for modulating and enhancing thermal and mechanical properties and biocompatibilities of coatings on implantable devices are disclosed. Implantable devices containing the enhanced thermal and mechanical properties and biocompatibilities are also described. The implantable devices can be used to treat a medical condition such as vulnerable plaque or restenosis.

Claims

1. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

modulating a polymer having a low glass transition temperature (T_g) to generate a polymer having an increased T_g by a step selected from the group consisting of

(a) altering the backbone of the polymer by reaction with a stiffening chemical agent;

(b) replacing the pendant groups of the polymer with less bulky linear groups or more bulky groups that increase potential rotation barrier of the polymer;

(c) increasing the molecular weight of the polymer;

(d) narrowing the molecular weight distribution of the polymer; and

(e) a combination of any of the processes as defined in (a)-(e), and

forming a coating comprising the polymer having an increased T_g onto the implantable device.

6. The method of claim 1 wherein the polymer having a low T_g is selected from the group consisting of poly(ester amide) (PEA), poly(glycerol sebacic acid) (PGS), low T_g PolyAspirin, and combinations thereof;

wherein the stiffening chemical agent is selected from the group consisting of short chain diacids, aromatic diols, aromatic diacids, styrene, and combinations thereof; and

wherein the less bulky groups are selected from the group consisting of hydrogen, methyl and ethyl.

14. The method of claim 1 wherein the coating further comprises a bioactive agent.

19. The method of claim 6 wherein the coating further comprises a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof.

24. A stent comprising a coating formed according to the method of claim 6.

32. A stent comprising a coating formed according to the method of claim 14.

37. A drug-delivery stent comprising a coating formed according to the method of claim 19.

42. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 24,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

50. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 32,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

55. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 37,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

2. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

forming a polymer blend by blending a polymer having a low glass transition temperature (T_g) with a minor amount of a polymer having a high T_g or a semi-crystalline polymer having a melting temperature (T_m), and

forming a coating comprising the polymer blend onto the implantable device.

7. The method of claim 2 wherein wherein the polymer having a low T_g is selected from the group consisting of poly(ester amide) (PEA), poly(glycerol sebacic acid) (PGS), low T_g PolyAspirin, and combinations thereof;

wherein the polymer having a high T_g is selected from the group consisting of polyhydroxyalkanoates, poly(3-hydroxybutyrate), poly(3-hydroxyvalerate) (PHV), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(D,L-lactide), poly(L-lactide), poly(glycolic acid), poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone) (PDS), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonate) and derivatives thereof, poly(tyrosine esters) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), poly(phosphazenes), high T_g PolyAspirin, poly(vinyl pyrrolidone) (PVP), and a combination thereof, and

wherein the semi-crystalline polymer is selected from the group consisting of high density polyethylene (HDPE), polycaprolactone (PCL), polypropylene, natural rubber (NR), polydimethyl siloxane (PDMS), polyethylene terephthalate (PET), nylon 6, polyetherimide (PEI), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP).

15. The method of claim 2 wherein the coating further comprises a bioactive agent.

20. The method of claim 7 wherein the coating further comprises a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof.

25. A stent comprising a coating formed according to the method of claim 7.

33. A stent comprising a coating formed according to the method of claim 15.

38. A drug-delivery stent comprising a coating formed according to the method of claim 20.

43. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 25,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

51. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 33,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

56. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 38,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

3. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

modulating a polymer having a high glass transition temperature (T_g) to generate a polymer having an decreased T_g by a step selected from the group consisting of

(a) replacing the pendant groups of the polymer with more bulky linear groups or less bulky groups that decrease potential rotation barrier of the polymer;

(b) decreasing the molecular weight of the polymer;

(c) broadening molecular weight distribution of the polymer; and

(d) a combination of any of the processes as defined in (a)-(c), and

forming a coating comprising the polymer having an decreased T_g onto the implantable device.

8. The method of claim 3 wherein the polymer having a high T_g is selected from the group consisting of polyhydroxyalkanoates, poly(3-hydroxybutyrate) (PHB), poly(3-hydroxyvalerate) (PHV), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(D,L-lactide), poly(L-lactide), poly(glycolic acid), poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone) (PDS), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonate) and derivatives thereof, poly(tyrosine esters) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), poly(phosphazenes), high T_g PolyAspirin, poly(vinyl pyrrolidone) (PVP), and a combination thereof.

16. The method of claim 3 wherein the coating further comprises a bioactive agent.

21. The method of claim 8 wherein the coating further comprises a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof.

26. A stent comprising a coating formed according to the method of claim 8.

34. A drug-delivery stent comprising a coating formed according to the method of claim 16.

39. A drug-delivery stent comprising a coating formed according to the method of claim 21.

44. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 26,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

52. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 34,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

57. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 39,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

4. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

forming a polymer blend by blending a polymer having a high glass transition temperature (T_g) with a minor amount of a polymer having a low T_g, and

forming a coating comprising the polymer blend onto the implantable device.

9. The method of claim 4 wherein the polymer having a high T_g is selected from the group consisting of polyhydroxyalkanoates, poly(3-hydroxybutyrate) (PHB), poly(3-hydroxyvalerate) (PHV), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(D,L-lactide), poly(L-lactide), poly(glycolic acid), poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(dioxanone) (PDS), poly(ortho esters), poly(anhydrides), poly(tyrosine carbonate) and derivatives thereof, poly(tyrosine esters) and derivatives thereof, poly(imino carbonates), poly(phosphoesters), poly(phosphazenes), high T_g PolyAspirin, poly(vinyl pyrrolidone) (PVP), and a combination thereof;

and

wherein the polymer having a low T_g is selected from the group consisting of poly(ester amide) (PEA), poly(glycerol sebacic acid) (PGS), polyethylene glycol (PEG), polyethylene oxide, polypropylene oxide (PPO), poly(ethylene glycol-co-propylene oxide) (PEG-PPO), low T_g PolyAspirin, low molecular weight DLPLA and combinations thereof.

17. The method of claim 4 wherein the coating further comprises a bioactive agent.

22. The method of claim 9 wherein the coating further comprises a 20 bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof.

27. A stent comprising a coating formed according to the method of claim 9.

35. A drug-delivery stent comprising a coating formed according to the method of claim 17.

40. A drug-delivery stent comprising a coating formed according to the method of claim 22.

45. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 27,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

53. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 35,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

58. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 40,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

5. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

forming a polymer blend by blending a polymer which is hydrophobic or comprises a hydrophobic component with a minor amount of a hydrophilic, non-fouling polymer, and

forming a coating comprising the polymer blend onto the implantable device.

10. The method of claim 5 wherein the hydrophilic, non-fouling polymer is selected from the group consisting of poly(ethylene glycol) (PEG), poly(ethylene oxide), poly(ethylene glycol-co-propylene oxide) (PEG-PPO), dextran, dextrin, poly(vinyl alcohol), poly(2-hydroxyethyl)methacrylate (HEMA), polyvinylpyrrolidone (PVP), poly(butyleneterephthalate-co-ethylene glycol) (PBT-PEG or POLYACTIVE™

), polyalkylene oxalates, pluronic acid, sulfonated polystyrene, block copolymers with a bioabsorbable block and a perfluoro chain, PEG-caprolactone, PEG-D,L-lactide, cellulosics, fibrin, fibrinogen, cellulose, starch, collagen, heparin and hyaluronic acid, polyvinyl alcohols, and a combination thereof.

18. The method of claim 5 wherein the coating further comprises a bioactive agent.

23. The method of claim 10 wherein the coating further comprises a bioactive agent selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), and combinations thereof.

28. A stent comprising a coating formed according to the method of claim 10.

36. A drug-delivery stent comprising a coating formed according to the method of claim 18.

41. A drug-delivery stent comprising a coating formed according to the method of claim 23.

46. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 28,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

54. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 36,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

59. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 41,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

11. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising

adding to the coating a material selected from the group consisting of chopped fibers, high surface/volume (S/V) ratio particulates, and the combination thereof,

wherein the chopped fibers are selected from the group consisting of polyester fibers;

PLA fibers;

PHA fibers;

PLGA fibers;

PGA fibers;

polydioxanone (PDS) fibers;

absorbable glass fibers;

carbon nanotube fibers;

polyalkylene fibers;

polyethylene vinyl alcohol (EVAL) fibers;

polypropylene fibers; and

polyethylenetelephthalate (PET) fibers, and

wherein the high surface/volume ratio particulates are selected from the group consisting of alumina particulates;

carbon nanoparticles;

carbon nanoshells;

carbon nanotubes;

hydroxyapatite;

tricalcium phosphate (TCP);

carbides;

nitrides;

TiO₂;

SiO₂;

calcium sulfate;

α

-tricalcium phosphate (TCP);

β

-tricalcium phosphate (TCP);

Carbonate-apatite (Dahlite);

titanium (Ti);

niobium (Nb);

tantalum (Ta);

platinum (Pt);

alloy of platinum and iridium (Ir) (Pt/Ir) and combination thereof.

29. A stent comprising a coating formed according to the method of claim 11.

47. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 29,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

12. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

forming a coating comprising a polymer having a low glass transition temperature (T_g) onto the implantable device, and

modulating the coating to increase the T_g by a step selected from the group consisting of

(a) altering the backbone of the polymer by reaction with a stiffening chemical agent;

(b) replacing the pendant groups of the polymer with less bulky linear groups or more bulky groups that increase potential rotation barrier of the polymer;

(c) increasing the molecular weight of the polymer; and

(d) a combination of any of the processes as defined in (a)-(c).

30. A stent comprising a coating formed according to the method of claim 12.

48. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 30,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

13. A method of modulating thermal, mechanical, and surface properties of a coating on an implantable device, comprising:

forming a coating comprising a polymer having a high glass transition temperature (T_g) onto the implantable device, and

modulating the coating to decrease the T_g by a step selected from the group consisting of

(a) replacing the pendant groups of the polymer with more bulky linear groups or less bulky groups that decrease potential rotation barrier of the polymer;

(b) decreasing the molecular weight of the polymer;

(c) broadening molecular weight distribution of the polymer; and

(d) a combination of any of the processes as defined in (a)-(c).

31. A stent comprising a coating formed according to the method of claim 13.

49. A method of treating a medical condition in a human being comprising implanting in the human being the stent of claim 31,

wherein the medical condition is selected from the group consisting of vulnerable plaque, restenosis, stenosis, atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.