COMPOSITIONS COMPRISING POROUS ARTICLES AND USES IN IMPLANTABLE MEDICAL DEVICES

Abstract

A composition comprising a first polymer having pores, nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer, and heparin covalently bonded to at least one of the first and second polymer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention will be understood from the following description, the appended claims and the accompanying drawings, in which:

FIG. 1 is a visual schematic of an embodiment of a biological mechanism by which heparin acts;

FIG. 2 is a schematic of the action of sirolimus on cell division; and

FIG. 3 is an experimental set-up for a heparinization process for poly(l-lactide).

Claims

1. A composition comprising: a first polymer having pores;nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer; andheparin covalently bonded to at least one of the first and second polymer.

2. The composition of claim 1, wherein the heparin is covalently bonded to one or both of the first and second polymers.

3. The composition of claim 1, wherein the polymer covalently bonded to heparin is biodegradable.

4. The composition of claim 1, wherein one or both of the first and second polymers is biodegradable.

5. The composition of claim 4, wherein the biodegradable polymer is chosen from poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

6. The composition of claim 4, wherein the biodegradable polymer is chosen from polylactides.

7. The composition of claim 1, wherein the first and second polymers are the same.

8. The composition of claim 1, wherein at least one of the first and second polymers comprises a blend of one or more polymers.

9. A device comprising a coating for at least a portion thereof, the coating comprising a composition comprising: a first polymer having pores;nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer; andheparin covalently bonded to at least one of the first and second polymers.

10. The device of claim 9, wherein the device is selected from sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.

11. The device of claim 9, wherein the device is implantable into a mammalian lumen.

12. The device of claim 9, wherein the device is a stent.

13. The device of claim 12, wherein the concentration of the at least one pharmaceutically active agent based on the surface area of the stent ranges from 0.1 to about 5 μg/mm2

14. The device of claim 12, wherein the concentration of the at least one pharmaceutically active agent based on the surface area of the stent ranges from about 0.7 μg/mm2 to about 3.0 μg/mm2

15. The device of claim 12, wherein the concentration of the at least one pharmaceutically active agent based on the surface area of the stent ranges from about 1.0 to about 1.8 μg/mm2

16. The device of claim 12, wherein the concentration of the at least one pharmaceutically active agent based on the surface area of the stent ranges from about 1.0 to about 1.4 μg/mm2.

17. The device of claim 9, wherein the coating contacts the medical device.

18. The device of claim 9, wherein the coating contacts at least one inner coating that contacts the medical device.

19. The device of claim 18, wherein the at least one inner coating is chosen from ceramics, nonbiodegradable polymers, metals, and carbon.

20. The device of claim 9, wherein the device further comprises a protective coating over the coating, wherein the protective coating is free of a pharmaceutically active agent.

21. The device of claim 20, wherein the protective coating comprises at least one biodegradable polymer.

22. The device of claim 9, wherein the at least one biodegradable polymer is covalently bonded to heparin.

23. The device of claim 9, wherein the device further comprises at least one additional coating comprising a polymer covalently bonded to heparin, the at least one additional coating comprising at least one pharmaceutically active agent.

24. The device of claim 23, wherein the polymer is biodegradable.

25. The device of claim 23, wherein the device comprises at least two additional coatings.

26. The device of claim 23, wherein the device comprises at least one additional coating and a protective coating.

27. The device of claim 9, wherein at least one of the first and second polymers degrades by hydrolysis in a natural intraluminal human body environment at preselected rates of degradation.

28. The device of claim 9, wherein the at least one pharmaceutically active agent is chosen from antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, anti-inflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.

29. The device of claim 9, wherein the at least one pharmaceutically active agent is chosen from paclitaxel, sirolimus, flavonoids, compounds of formula A

30. The device of claim 29, wherein the flavonoid is selected from chalcones, dihydrochalcones, flavanones, flavonols, dihydroflavonols, flavones, flavanols, isoflavones, neoflavones, aurones, anthocyanidins, proanthocyanidins and isoflavanes.

31. The device of claim 29, wherein the flavonoid is selected from flavanones, flavonols, and isoflavones.

32. The device of claim 29, wherein the flavonoid is selected from narigenin, naringin, eriodictyol, hesperetin, hesperidin (esperidine), kampferol, quercetin, rutin, cyanidol, meciadonol, catechin, epi-gallocatechin-gallate, taxifolin (dihydroquercetin), genistein, genistin, daidzein, biochanin, glycitein, chrysin, diosmin, luetolin, apigenin, tangeritin and nobiletin.

33. The device of claim 29, wherein the at least one pharmaceutically active agent is paclitaxel.

34. The device of claim 29, wherein the at least one pharmaceutically active agent is sirolimus.

35. The device of claim 29, wherein the at least one pharmaceutically active agent is genistein.

36. A device comprising a coating, comprising: a polymer having pores;nanoparticles dispersed within the pores of the polymer, the nanoparticles comprising at least one pharmaceutically active agent;wherein the at least one pharmaceutically active agent is chosen from composition comprising at least one pharmaceutically active agent selected from genistein or compounds having the structure of Formula A and Formula B below:

37. The device of claim 36, wherein the nanoparticles further comprise a polymer that is the same or different from the porous polymer, the nanoparticles being porous or nonporous.

38. The device of claim 36, wherein at least one of the nanoparticulate polymer and the porous polymer is biodegradable.

39. The device of claim 38, wherein the biodegradable polymer is chosen from poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

40. The device of claim 36, wherein at least one of the nanoparticulate polymer and the porous polymer further comprises heparin.

41. The device of claim 40, wherein the heparin is covalently bonded to the polymer.

42. The device of claim 36, wherein both the nanoparticulate polymer and the porous polymer comprise a biodegradable polymer covalently bound to heparin.

43. A method of making an implantable medical device comprising: coating the implantable medical device with a mixture comprising: a polymer, polymer suspension, or polymer-containing solution, anda solvent;changing the temperature of the mixture to induce a phase separation of a polymer-rich phase and a polymer-poor phase; andremoving the solvent to form a porous polymer coating on the device.

44. The method of claim 43, wherein the method further comprises impregnating the pores of the polymer with nanoparticles comprising at least one pharmaceutically active agent.

45. The method of claim 44, wherein the nanoparticles further comprise a polymer which may be the same or different as the porous polymer.

46. The method of claim 45, wherein at least one of the porous polymer or the nanoparticulate polymer is covalently bound to heparin.

47. The method of claim 45, wherein at least one of the porous polymer or the nanoparticulate polymer is biodegradable.

48. The method of claim 45, wherein at least one of the porous polymer or the nanoparticulate polymer comprises one or more of poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

49. The method of claim 45, wherein both the nanoparticulate polymer and the porous polymer comprises a biodegradable polymer covalently bonded to heparin.

50. A method of treating at least one disease or condition associated with vascular injury or angioplasty comprising, implanting in a subject in need thereof a medical device having a coating for at least a portion thereof comprising a composition comprising: a first polymer having pores;nanoparticles dispersed within the pores of the first polymer, the nanoparticles comprising a second polymer and at least one pharmaceutically active agent dispersed in the second polymer; andheparin covalently bonded to at least one of the first and second polymer.

51. The method of claim 50, wherein the heparin is covalently bonded to both the first and second polymers.

52. The method of claim 51, wherein the polymer covalently bonded to heparin is biodegradable.

53. The method of claim 50, wherein one or both of the first and second polymers is biodegradable.

54. The method of claim 53, wherein the biodegradable polymer is chosen from poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

55. The method of claim 53, wherein the biodegradable polymer is chosen from polylactides.

56. The method of claim 50, wherein the first and second polymers are the same.

57. The method of claim 50, wherein at least one of the first and second polymers comprises a blend of one or more polymers.

58. The method of claim 50, wherein the at least one disease or condition is a proliferative disorder.

59. The method of claim 58, wherein the proliferative disorder is restenosis.

60. The method of claim 58, wherein the proliferative disorder is a tumor.

61. The method of claim 58, wherein the proliferative disorder comprises the proliferation of smooth muscle cells.

62. The method of claim 58, wherein the at least one disease or condition is an inflammatory disease.

63. The method of claim 58, wherein the at least one disease or condition is an autoimmune disease.

64. The method of claim 58, wherein the at least one disease or condition is neointima and neointimal hyperplasia.

65. The method of claim 58, wherein the at least one disease or condition is selected from thrombosis, embolism, and platelet accumulation.

66. A medical treatment device having a surface having a coating on the surface, the coating comprising: a first polymer having pores;nanoparticles comprised of a second polymer dispersed within the pores of the first polymer, the nanoparticles further comprising at least one pharmaceutically active agent;wherein the at least one pharmaceutically active agent is chosen from heparin, flavonoids, paclitaxel and its analogs, rapamycin and its analogs and benzopyran-4-one compounds.

67. The device of claim 66 wherein the at least one pharmaceutically active agent is covalently bonded to the second polymer.

68. The device of claim 67 wherein the second polymer contains an electrophilic group and the pharmaceutically active agent contains a nucleophilic group reactive with the electrophilic group to covalently bond the pharmaceutically active agent to the polymer.

69. The device of claim 67 wherein the second polymer is chosen from poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

70. The device of claim 69 wherein the pharmaceutically active agent is a flavonoid.

71. The device of claim 70 wherein the pharmaceutically active agent is genistein.

72. The device of claim 66 wherein the at least one pharmaceutically active agent is covalently bonded to the first polymer.

73. The device of claim 72 wherein the second polymer contains an electrophilic group and the pharmaceutically active agent contains a nucleophilic group reactive with the electrophilic group to covalently bond the pharmaceutically active agent to the polymer.

74. The device of claim 72 wherein the second polymer is chosen from poly(l-lactide), racemic polylactide, poly(l-lactide-co-glycolide), racemic poly(l-lactide-co-glycolide), poly(l-lactide-co-caprolactone poly(d,l-lactide-co-caprolactone), poly(l-lactide-co-trimethylene carbonate) and poly(d,l-lactide-co-trimethylene carbonate).

75. The device of claim 74 wherein the pharmaceutically active agent is a flavonoid.

76. The device of claim 75 wherein the pharmaceutically active agent is genistein.

77. The device of claim 66 wherein the first and second polymers are the same or different.

78. The device of claim 67 wherein a pharmaceutically active agent is covalently bonded to the first polymer.