Expandable medical device with beneficial agent matrix formed by a multi solvent system

• US 20050100577A1
• Filed: 04/22/2004
• Published: 05/12/2005
• Est. Priority Date: 11/10/2003
• Status: Abandoned Application

• Current Assignee: Innovational Holdings, LLC
• Original Assignee: Innovational Holdings, LLC
• Inventors: Markey, Micheline Lisa, Shanley, John F., Parker, Theodore L.
• Application Number:
  US10/830,566
• Publication Number:
  US 20050100577A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2/915 with bands having a meander structure, adjacent bands being connected to each other
• CPC Class Codes: A61F 2002/91541 Adjacent bands are arranged out of phase
• CPC Class Codes: A61F 2210/0076 multilayered, e.g. laminated structures
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/61 containing two or more active agents in different layers
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/146 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

A multi solvent drug delivery matrix formation method is used to place layers into a reservoir in a stent in a stepwise manner to achieve extended delivery of water soluble, sensitive, or difficult to deliver drugs. The multi solvent matrix formation method allows the formation of a drug reservoir with a layered morphology in which the mixing between layers is limited to allow the different layers to perform different functions in controlling drug delivery. A stent having a drug delivery matrix includes a first beneficial agent layer affixed to the stent by depositing a first solution of a first polymer and a first solvent, and a second beneficial agent layer affixed to the first beneficial agent layer by depositing a second solution of a second polymer and a second solvent. The second solvent is selected so that the first polymer is substantially insoluble in the second solvent to prevent degradation of the first polymer during deposition of the second polymer. A therapeutic agent is provided in the first beneficial agent layer or the second beneficial agent layer to form a drug delivery matrix.

Claims

1. An implantable medical device comprising:

an implantable device body having a plurality of openings;

at least one base layer contained in the plurality of openings comprising a first polymer material that is soluble in a first solvent; and

at least one therapeutic layer contained in the plurality of openings comprising a first therapeutic agent and a second polymer material both of which are soluble in a common second solvent in which the first polymer material is substantially insoluble.

2. The device of claim 1, wherein the at least one therapeutic agent is a water soluble drug.

3. The device of claim 2, wherein the at least one therapeutic agent is 2-chlorodeoxyadenosine.

4. The device of claim 2, wherein the at least one therapeutic agent is insulin.

5. The device of claim 1, wherein the at least one therapeutic agent and the second polymer material are soluble in dimethyl sulfoxide and the first polymer material is soluble in one or more of anisole, trifluoroethanol, methylene chloride, hexafluoroisopropanol (HFIP), trifluoroethanol (TFE), heptafluorobutanol (HFB), and chloroform, or mixtures thereof.

6. The device of claim 1, further comprising a cap layer formed of a third polymer material that is soluble in a third solvent in which the at least one therapeutic agent is substantially insoluble.

7. The device of claim 6, wherein the cap layer comprises a second therapeutic agent which is soluble in the third solvent.

8. The device of claim 7, wherein the second therapeutic agent is paclitaxel.

9. The device of claim 6, wherein the first and third solvents are the same.

10. The device of claim 1, wherein the first, second, and third polymer materials are bioerodible polymers.

11. The device of claim 10, wherein the first polymer material or the third polymer material is a slower degrading polymer than the second polymer material to provide directional delivery of the at least one therapeutic agent.

12. The device of claim 1, wherein the base layer is annealed to resist dissolution.

13. The device of claim 1, wherein the implantable medical device is a stent.

14. The device of claim 13, wherein the plurality of openings are radially oriented non-deforming through holes.

15. The device of claim 1, wherein the plurality of openings each have a volume of about 0.1 nanoliters to about 50 nanoliters.

16. The device of claim 1, wherein the at least one base layer does not include a substantial amount of the at least one therapeutic agent.

17. The device of claim 1, wherein the at least one therapeutic agent is arranged to be delivered over an administration period of about 7 days or more.

18. An implantable medical device comprising:

an implantable device body having a plurality of openings;

at least one therapeutic agent layer contained in the plurality of openings, wherein the therapeutic agent layer is formed with a first polymer, a first solvent, and a first therapeutic agent; and

at least one cap layer contained in the plurality of openings adjacent the at least one therapeutic agent layer, the at least one cap layer is formed with a second polymer and a second solvent, wherein the first therapeutic agent is at most marginally soluble in the second solvent.

19. The device of claim 18, wherein the at least one therapeutic agent is a water soluble drug.

20. The device of claim 19, wherein the at least one therapeutic agent is 2-chlorodeoxyadenosine.

21. The device of claim 19, wherein the at least one therapeutic agent is insulin.

22. The device of claim 18, wherein the cap layer includes a second therapeutic agent which is soluble in the second solvent.

23. The device of claim 22, wherein the second therapeutic agent is paclitaxel.

24. The device of claim 18, further comprising at least one base layer contained in the plurality of holes adjacent the at least one therapeutic agent layer, wherein the base layer is formed with a third polymer and a third solvent.

25. The device of claim 24, wherein the second and third polymers solvents are the same.

26. The device of claim 24, wherein the first, second, and third polymers are bioerodible polymers.

27. The device of claim 18, wherein the implantable medical device is a stent.

28. The device of claim 27, wherein the plurality of holes are radially oriented non-deforming through holes.

29. The device of claim 18, wherein the plurality of openings each have a volume of about 0.1 nanoliters to about 50 nanoliters.

30. The device of claim 18, wherein the at least one therapeutic agent is arranged to be delivered over an administration period of about 7 days or more.

31. The device of claim 18, wherein the at least one cap layer does not include a substantial amount of the at least one therapeutic agent.

32. A method of loading an implantable medical device with a controlled release polymer drug matrix:

depositing a first solution of a first polymer, a first therapeutic agent, and a first solvent in which the first polymer and the first therapeutic agent are both soluble;

evaporating the first solvent;

depositing a second solution of a second polymer, and a second solvent in which the second polymer is soluble, wherein the first therapeutic agent is substantially insoluble in the second solvent; and

evaporating the second solvent.

33. The method of claim 32, wherein the first solution and the second solution are deposited in a plurality of openings in the medical device.

34. The method of claim 33, wherein the plurality of openings are radially oriented non-deforming through holes.

35. The method of claim 32, wherein the first therapeutic agent is a water soluble drug.

36. The method of claim 35, wherein the first therapeutic agent is 2-chlorodeoxyadenosine.

37. The method of claim 35, wherein the first therapeutic agent is insulin.

38. The method of claim 32, wherein the second solution includes a second therapeutic agent which is soluble in the second solvent.

39. The method of claim 38, wherein the second therapeutic agent is paclitaxel.

40. The method of claim 32, wherein the first and second polymer materials are bioerodible polymers.

41. The method of claim 32, wherein the implantable medical device is a stent.

42. A method of loading an implantable medical device with a controlled release polymer drug matrix:

depositing a first solution of a first polymer and a first solvent in which the first polymer is soluble;

evaporating the first solvent;

depositing a second solution of a second polymer, a first therapeutic agent, and a second solvent in which the second polymer and the first therapeutic agent are both soluble, wherein the first polymer is substantially insoluble in the second solvent; and

evaporating the second solvent.

43. The method of claim 42, wherein the first solution and the second solution are deposited in a plurality of openings in the medical device.

44. The method of claim 43, wherein the plurality of openings are radially oriented non-deforming through holes.

45. The method of claim 42, wherein the first therapeutic agent is a water soluble drug.

46. The method of claim 42, wherein the first therapeutic agent is 2-chlorodeoxyadenosine.

47. The method of claim 42, wherein the first therapeutic agent is insulin.

48. The method of claim 42, wherein the first solution includes a second therapeutic agent which is soluble in the first solvent.

49. The method of claim 42, wherein the second therapeutic agent is paclitaxel.

50. The method of claim 42, wherein the first and second polymer materials are bioerodible polymers.

51. The method of claim 42, wherein the implantable medical device is a stent.

52. The method of claim 42, wherein the steps of depositing the first solution and evaporating the first solvent form at least one base layer and the subsequent deposition of the second solution results in an insubstantial amount of the first therapeutic agent in the base layer.

53. A method of loading an implantable medical device with a controlled release polymer drug matrix in a plurality of layers:

creating a first layer by delivering a first solution of a first polymer and a first solvent and evaporating the first solvent;

creating a second layer by delivering a second solution of a second polymer and a second solvent, wherein the second solvent does not significantly dissolve the first layer; and

providing a therapeutic agent in at least one of the first and second layers.

54. The method of claim 53, wherein the first polymer is selected from the group consisting of poly-L-lactide and PLGA and the second polymer is poly(vinylpyrrolidone).

55. The method of claim 53, wherein the first layer and the second layer are deposited in a plurality of openings in the medical device.

56. The method of claim 55, wherein the plurality of openings are radially oriented non-deforming through holes.

57. The method of claim 53, wherein the therapeutic agent is a water soluble drug.

58. The method of claim 57, wherein the therapeutic agent is 2-chlorodeoxyadenosine.

59. The method of claim 57, wherein the therapeutic agent is insulin.

60. The method of claim 53, wherein the first and second polymer materials are bioerodible polymers.

61. The method of claim 53, wherein the implantable medical device is a stent.

62. An implantable stent comprising:

an expandable stent body;

a first beneficial agent layer affixed to the stent by depositing a first solution comprising a first polymer and a first solvent, wherein the first polymer is soluble in the first solvent;

a second beneficial agent layer affixed to the first beneficial agent layer by depositing a second solution comprising a second polymer and a second solvent, wherein the second polymer is soluble in the second solvent and the first polymer is substantially insoluble in the second solvent; and

a therapeutic agent provided in the first beneficial agent layer or the second beneficial agent layer, wherein the therapeutic agent is soluble in the first or second solvent.

63. The stent of claim 62, wherein the first and second beneficial agent layers are deposited in a plurality of openings in the stent body.

64. The stent of claim 63, wherein the plurality openings are radially oriented non-deforming through holes.

65. The stent of claim 62, wherein the therapeutic agent is a water soluble drug.

66. The stent of claim 65, wherein the therapeutic agent is 2-chlorodeoxyadenosine.

67. The stent of claim 65, wherein the therapeutic agent is insulin.

68. The stent of claim 62, wherein the therapeutic agent is soluble in the first solvent and is substantially insoluble in the second solvent.

69. The stent of claim 62, wherein the therapeutic agent is soluble in the second solvent and is substantially insoluble in the first solvent 70. The device of claim 63, wherein the plurality of openings each have a volume of about 0.1 nanoliters to about 50 nanoliters.

70. The device of claim 65, wherein the therapeutic agent is arranged to be delivered from the stent over an administration period of about 7 days or more.

71. An implantable medical device comprising:

an implantable device body having a plurality of openings;

at least two hydrophobic layers of matrix material in the openings; and

at least one hydrophilic therapeutic agent layer in the openings positioned between the hydrophobic layers.

72. A method of loading an implantable medical device with a controlled release polymer drug matrix in a plurality of layers:

creating a base layer by delivering a first solution of a first polymer and a first solvent and evaporating the first solvent;

annealing the base layer;

creating a therapeutic agent layer by delivering a second solution of a second polymer, a therapeutic agent, and a second solvent.

73. The method of claim 72, wherein the base layer contains substantially no therapeutic agent.

74. The method of claim 72, wherein the steps of delivering the first solution, evaporating the first solvent, and annealing are repeated for multiple layers of the base layer.