Drug eluting lead systems

• US 20080195227A1
• Filed: 02/08/2007
• Published: 08/14/2008
• Est. Priority Date: 02/08/2007
• Status: Active Grant

• Current Assignee: Neuropace Inc.
• Original Assignee: Neuropace Inc.
• Inventors: Tcheng, Thomas K., Chao, Daniel, Morrell, Martha J., Boling, C. Lance, Wingeier, Brett M., Pless, Benjamin D.
• Granted Patent: US 7,844,345 B2
• Time in Patent Office: Days
• US Class Current: 623/23.71
• CPC Class Codes: A61N 1/0529 Electrodes for brain stimulation
• CPC Class Codes: A61N 1/0536 Preventing neurodegenerative response or inflammatory reaction
• CPC Class Codes: A61N 1/0539 Anchoring of brain electrode systems, e.g. within burr hole
• CPC Class Codes: A61N 1/0551 Spinal or peripheral nerve electrodes
• CPC Class Codes: A61N 1/36082 Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
• CPC Class Codes: B22F 2003/241 Chemical after-treatment on the surface
• CPC Class Codes: B22F 2003/242 Coating
• CPC Class Codes: B22F 2998/10 Processes characterised by the sequence of their steps
• CPC Class Codes: B22F 3/10 Sintering only
• CPC Class Codes: B22F 3/24 After-treatment of workpieces or articles B22F3/1146 takes precedence

Abstract

Medical electrical lead systems and related methods are described. The lead systems may be configured to be at least partially implanted in neural tissue of a subject, such as a brain of a subject. Some variations of the lead systems may comprise a lead body, an electrode connected to the lead body, and a bioactive agent. The electrode and/or lead body may comprise a substrate, and the bioactive agent may be supported by the substrate (e.g., by a substantial portion of the area of the substrate). Examples of bioactive agents that may be used in the lead system include antiproliferative agents, bactericidal agents, bacteriostatic agents, antiepileptic agents, and/or antifungal agents. Methods described herein may comprise coating a lead body and/or an electrode of a medical electrical lead system with at least one bioactive agent, where the lead body and the electrode are connected to each other.

Claims

1. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body;

a first electrode connected to the lead body and comprising a first substrate; and

a first antiproliferative agent supported by a substantial portion of the area of the first substrate of the first electrode.

2. The lead system of claim 1, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

3. The lead system of claim 1, wherein the first antiproliferative agent is capable of limiting or preventing glial encapsulation of at least one of the lead body and the first electrode.

4. The lead system of claim 1, wherein the first antiproliferative agent is selected from the group consisting of bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, and combinations thereof.

5. The lead system of claim 1, wherein the first antiproliferative agent comprises a bone morphogenic protein.

6. The lead system of claim 1, wherein the first antiproliferative agent comprises ciliary neurotrophic factor.

7. The lead system of claim 1, wherein the first antiproliferative agent comprises ribavirin.

8. The lead system of claim 1, wherein the first antiproliferative agent comprises sirolimus.

9. The lead system of claim 1, wherein the first antiproliferative agent comprises mycophenolate.

10. The lead system of claim 1, wherein the first antiproliferative agent comprises mofetil.

11. The lead system of claim 1, wherein the first antiproliferative agent comprises azathioprine.

12. The lead system of claim 1, wherein the first antiproliferative agent comprises paclitaxel.

13. The lead system of claim 1, wherein the first antiproliferative agent comprises cyclophosphamide.

14. The lead system of claim 1, further comprising a second electrode connected to the lead body.

15. The lead system of claim 14, wherein the second electrode comprises a second substrate, and the lead system further comprises a bioactive agent that is supported by the second substrate.

16. The lead system of claim 15, wherein the bioactive agent comprises a second antiproliferative agent.

17. The lead system of claim 16, wherein the second antiproliferative agent is different from the first antiproliferative agent.

18. The lead system of claim 15, wherein the bioactive agent is selected from the group consisting of bactericidal agents, bacteriostatic agents, and combinations thereof.

19. The lead system of claim 15, wherein the bioactive agent is selected from the group consisting of quinolone, fluoroquinolone, beta-lactam, aminoglycoside, penicillin, macrolide, monobactam, lincosamide, tetracycline, cephalosporin, lipopeptide, streptogramin, carbapenem, sulfonamide, aminoglycoside, oxalodinone, nitrofuran, ketolide, glycylcycline families of antibiotics, and combinations thereof.

20. The lead system of claim 15, wherein the bioactive agent comprises silver ions.

21. The lead system of claim 1, wherein the lead system comprises more than two electrodes that are connected to the lead body.

22. The lead system of claim 1, wherein the first antiproliferative agent contacts the first substrate.

23. The lead system of claim 1, wherein the first antiproliferative agent is in the form of a coating on the first substrate.

24. The lead system of claim 1, further comprising at least one polymer supported by the first substrate.

25. The lead system of claim 24, wherein the at least one polymer is selected from the group consisting of poly(3,4-ethylenedioxythiopene), poly(3,4-ethylenedioxythiopene) poly(styrenesulfonate), and combinations thereof.

26. The lead system of claim 24, wherein the first antiproliferative agent is dispersed throughout the at least one polymer.

27. The lead system of claim 24, wherein the first antiproliferative agent is encapsulated within the at least one polymer.

28. The lead system of claim 24, wherein the at least one polymer is in the form of a layer over the first antiproliferative agent.

29. The lead system of claim 24, wherein the at least one polymer is bioerodible.

30. The lead system of claim 1, further comprising a material that is supported by the first substrate and that is different from the first antiproliferative agent.

31. The lead system of claim 30, wherein the material comprises silicone.

32. The lead system of claim 31, wherein the first antiproliferative agent is encapsulated within the silicone.

33. The lead system of claim 30, wherein the material comprises at least one bioerodible polyanhydride or polyanhydride compound.

34. The lead system of claim 33, wherein the at least one bioerodible polyanhydride or polyanhydride compound is selected from the group consisting of fatty acid-terminated polyanhydrides, poly(fatty acid dimer), copolymers of poly(sebacic acid) and fatty acid, copolymers of dimer fatty acids, and combinations thereof.

35. The lead system of claim 33, wherein the at least one bioerodible polyanhydride or polyanhydride compound is selected from the group consisting of poly[1,3-bis(carboxyphenoxy)propane-co-sebacic-acid], poly(fumaric acid), poly(sebacic acid), poly(erucic acid dimer), copolymers of fumaric acid and sebacic acid, poly(sebacic-co-ricinoleic acid maleate), poly(sebacic-co-ricinoleic acid succinate), poly(sebacic-co-12-hydroxystearic acid succinate), and combinations thereof.

36. The lead system of claim 30, wherein the material comprises at least one hydrogel supported by the first substrate.

37. The lead system of claim 30, wherein the material is in the form of a layer over the first antiproliferative agent.

38. The lead system of claim 30, wherein the material is bioerodible.

39. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body comprising a substrate;

an electrode connected to the lead body; and

at least one antiproliferative agent supported by the substrate of the lead body.

40. The lead system of claim 39, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

41. The lead system of claim 39, wherein the at least one antiproliferative agent is capable of limiting or preventing glial encapsulation of at least one of the lead body and the electrode.

42. The lead system of claim 39, wherein the at least one antiproliferative agent is selected from the group consisting of bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, and combinations thereof.

43. The lead system of claim 39, wherein the at least one antiproliferative agent comprises a bone morphogenic protein.

44. The lead system of claim 39, wherein the at least one antiproliferative agent comprises ciliary neurotrophic factor.

45. The lead system of claim 39, wherein the at least one antiproliferative agent comprises ribavirin.

46. The lead system of claim 39, wherein the at least one antiproliferative agent comprises sirolimus.

47. The lead system of claim 39, wherein the at least one antiproliferative agent comprises mycophenolate.

48. The lead system of claim 39, wherein the at least one antiproliferative agent comprises mofetil.

49. The lead system of claim 39, wherein the at least one antiproliferative agent comprises azathioprine.

50. The lead system of claim 39, wherein the at least one antiproliferative agent comprises paclitaxel.

51. The lead system of claim 39, wherein the at least one antiproliferative agent comprises cyclophosphamide.

52. The lead system of claim 39, wherein the lead system comprises a plurality of electrodes that are connected to the lead body.

53. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body;

an electrode connected to the lead body and comprising a substrate; and

at least one antiepileptic agent supported by a substantial portion of the area of the substrate of the electrode.

54. The lead system of claim 53, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

55. The lead system of claim 53, wherein the lead system comprises a plurality of electrodes that are connected to the lead body.

56. The lead system of claim 53, wherein the at least one antiepileptic agent is selected from the group consisting of acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, and combinations thereof.

57. The lead system of claim 53, further comprising a material that is supported by the first substrate and that is different from the at least one antiepileptic agent.

58. The lead system of claim 57, wherein the at least one antiepileptic agent is dispersed or encapsulated in the material.

59. The lead system of claim 57, wherein the material is in the form of a layer over the at least one antiepileptic agent.

60. The lead system of claim 57, wherein the material comprises a polymer.

61. The lead system of claim 60, wherein the polymer is selected from the group consisting of poly(3,4-ethylenedioxythiopene), poly(3,4-ethylenedioxythiopene) poly(styrenesulfonate), and combinations thereof.

62. The lead system of claim 60, wherein the polymer is bioerodible.

63. The lead system of claim 53, wherein the at least one antiepileptic agent contacts the substrate.

64. The lead system of claim 53, wherein the at least one antiepileptic agent is in the form of a coating on the substrate.

65. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body comprising a substrate;

an electrode connected to the lead body; and

at least one antiepileptic agent supported by the substrate of the lead body.

66. The lead system of claim 65, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

67. The lead system of claim 65, wherein the lead system comprises a plurality of electrodes that are connected to the lead body.

68. The lead system of claim 65, wherein the at least one antiepileptic agent is selected from the group consisting of acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, and combinations thereof.

69. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body;

an electrode connected to the lead body; and

at least one antifungal agent,

wherein at least one of the lead body and the electrode comprises a substrate, and the at least one antifungal agent is supported by the substrate.

70. The lead system of claim 69, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

71. The lead system of claim 69, wherein the lead system comprises a plurality of electrodes that are connected to the lead body.

72. The lead system of claim 69, wherein the at least one antifungal agent is selected from the group consisting of amphotericin B, anidulafungin, butenafine, butoconazole, caspofungin, ciclopirox, clioquinol, econazole, fluconazole, flucytosine, griseofulvin, traconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, sulconazole, sulfanilamide, terbinafine, terconazole, undecylenic, voriconazole, and combinations thereof.

73. A method comprising:

at least partially implanting a lead system in neural tissue of a subject,

wherein the lead system comprises a lead body, an electrode connected to the lead body and comprising a substrate, and at least one antiproliferative agent supported by a substantial portion of the area of the substrate of the electrode.

74. The method of claim 73, wherein the method comprises at least partially implanting the lead system in a brain of the subject.

75. The method of claim 73, wherein the at least one antiproliferative agent is capable of limiting or preventing glial encapsulation of at least one of the lead body and the electrode.

76. The method of claim 73, wherein the at least one antiproliferative agent is selected from the group consisting of bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, and combinations thereof.

77. The method of claim 73, wherein the at least one antiproliferative agent comprises a bone morphogenic protein.

78. The method of claim 73, wherein the at least one antiproliferative agent comprises ciliary neurotrophic factor.

79. The method of claim 73, wherein the at least one antiproliferative agent comprises ribavirin.

80. The method of claim 73, wherein the at least one antiproliferative agent comprises sirolimus.

81. The method of claim 73, wherein the at least one antiproliferative agent comprises mycophenolate.

82. The method of claim 73, wherein the at least one antiproliferative agent comprises mofetil.

83. The method of claim 73, wherein the at least one antiproliferative agent comprises azathioprine.

84. The method of claim 73, wherein the at least one antiproliferative agent comprises paclitaxel.

85. The method of claim 73, wherein the at least one antiproliferative agent comprises cyclophosphamide.

86. The method of claim 73, wherein the lead system is configured to release the at least one antiproliferative agent when the lead system is at least partially implanted in neural tissue of a subject.

87. The method of claim 73, wherein the lead system further comprises a material that is supported by the substrate and that is different from the at least one antiproliferative agent.

88. The method of claim 87, wherein the material is bioerodible.

89. The method of claim 88, wherein erosion of the bioerodible material, when the lead system is at least partially implanted in neural tissue of a subject, results in the release of the at least one antiproliferative agent into the neural tissue of the subject.

90. A method comprising:

at least partially implanting a lead system in neural tissue of a subject,

wherein the lead system comprises a lead body comprising a substrate, an electrode connected to the lead body, and at least one antiproliferative agent supported by the substrate of the lead body.

91. The method of claim 90, wherein the method comprises at least partially implanting the lead system in a brain of the subject.

92. The method of claim 90, wherein the at least one antiproliferative agent is capable of limiting or preventing glial encapsulation of at least one of the lead body and the electrode.

93. The method of claim 90, wherein the at least one antiproliferative agent is selected from the group consisting of bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, and combinations thereof.

94. The method of claim 90, wherein the at least one antiproliferative agent comprises a bone morphogenic protein.

95. The method of claim 90, wherein the at least one antiproliferative agent comprises ciliary neurotrophic factor.

96. The method of claim 90, wherein the at least one antiproliferative agent comprises ribavirin.

97. The method of claim 90, wherein the at least one antiproliferative agent comprises sirolimus.

98. The method of claim 90, wherein the at least one antiproliferative agent comprises mycophenolate.

99. The method of claim 90, wherein the at least one antiproliferative agent comprises mofetil.

100. The method of claim 90, wherein the at least one antiproliferative agent comprises azathioprine.

101. The method of claim 90, wherein the at least one antiproliferative agent comprises paclitaxel.

102. The method of claim 90, wherein the at least one antiproliferative agent comprises cyclophosphamide.

103. A method comprising:

at least partially implanting a lead system in neural tissue of a subject,

wherein the lead system comprises a lead body, an electrode connected to the lead body and comprising a substrate, and at least one antiepileptic agent supported by a substantial portion of the area of the substrate of the electrode.

104. The method of claim 103, wherein the method comprises at least partially implanting the lead system in a brain of a subject.

105. The method of claim 103, wherein the at least one antiepileptic agent is selected from the group consisting of acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, and combinations thereof.

106. The method of claim 103, wherein the lead system is configured to release the at least one antiepileptic agent when the lead system is at least partially implanted in neural tissue of a subject.

107. The method of claim 103, wherein the lead system further comprises a material that is supported by the substrate and that is different from the at least one antiepileptic agent.

108. The method of claim 107, wherein the material is bioerodible.

109. The method of claim 108, wherein erosion of the bioerodible material when the lead system is at least partially implanted in neural tissue of a subject results in the release of the at least one antiepileptic agent into the neural tissue of the subject.

110. A method comprising:

at least partially implanting a lead system in neural tissue of a subject,

wherein the lead system comprises a lead body comprising a substrate, an electrode connected to the lead body, and at least one antiepileptic agent supported by the substrate of the lead body.

111. The method of claim 110, wherein the method comprises at least partially implanting the lead system in a brain of a subject.

112. The method of claim 110, wherein the at least one antiepileptic agent is selected from the group consisting of acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, and combinations thereof.

113. A method comprising:

at least partially implanting a lead system in neural tissue of a subject, the lead system comprising a lead body, an electrode connected to the lead body, and at least one antifungal agent,

wherein at least one of the lead body and the electrode comprises a substrate, and the at least one antifungal agent is supported by the substrate.

114. The method of claim 113, wherein the method comprises at least partially implanting the lead system in a brain of the subject.

115. The method of claim 113, wherein the at least one antifungal agent is selected from the group consisting of amphotericin B, anidulafungin, butenafine, butoconazole, caspofungin, ciclopirox, clioquinol, econazole, fluconazole, flucytosine, griseofulvin, traconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, sulconazole, sulfanilamide, terbinafine, terconazole, undecylenic, voriconazole, and combinations thereof.

116. A method comprising:

at least partially implanting a lead system comprising a lead body and an electrode connected to the lead body in neural tissue of a subject,

wherein the implantation of the lead system results in the formation of at least one microlesion in the neural tissue of the subject, and at least one of the lead body and the electrode comprises a bioactive agent that is adapted to inhibit neuronal regeneration, neuronal reconnection, or both neuronal regeneration and neuronal reconnection.

117. The method of claim 116, wherein the method comprises at least partially implanting the lead system in a brain of the subject.

118. A method comprising:

coating a substantial portion of the area of an electrode of a medical electrical lead system comprising the electrode and a lead body connected to the electrode,

wherein the substantial portion of the area of the electrode is coated with at least one bioactive agent selected from the group consisting of antiproliferative agents, antiepileptic agents, and combinations thereof.

119. The method of claim 118, wherein coating the substantial portion of the area of the electrode comprises using a coating method selected from the group consisting of vapor deposition, ionic plasma deposition, dipping, and combinations thereof.

120. The method of claim 119, wherein vapor deposition comprises physical vapor deposition.

121. A method comprising:

coating a lead body of a medical electrical lead system comprising the lead body and an electrode connected to the lead body,

wherein the lead body is coated with at least one bioactive agent selected from the group consisting of antiproliferative agents, antiepileptic agents, and combinations thereof.

122. The method of claim 121, wherein coating the lead body comprises using a coating method selected from the group consisting of vapor deposition, ionic plasma deposition, dipping, and combinations thereof.

123. The method of claim 122, wherein vapor deposition comprises physical vapor deposition.

124. A method comprising:

coating at least one of a lead body and an electrode of a medical electrical lead system with at least one antifungal agent,

wherein the lead body is connected to the electrode.

125. The method of claim 124, wherein coating at least one of the lead body and the electrode comprises using a coating method selected from the group consisting of vapor deposition, ionic plasma deposition, dipping, and combinations thereof.

126. The method of claim 125, wherein vapor deposition comprises physical vapor deposition.

127. A medical electrical lead system configured to be at least partially implanted in neural tissue of a subject, comprising:

a lead body;

an electrode connected to the lead body and comprising a sintered metal characterized by a plurality of pores;

the electrode adapted to accept and act as a reservoir for a bioactive agent and the pores in the sintered metal adapted to release the bioactive agent from the reservoir into the neural tissue.

128. The lead system of claim 127, wherein the bioactive agent is selected from the group consisting of:

an antiproliferative agent, an antiepileptic agent, an antifungal agent, and combinations thereof.

129. The lead system of claim 128, wherein the bioactive agent is selected from the group consisting of:

bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, amphotericin B, anidulafungin, butenafine, butoconazole, caspofungin, ciclopirox, clioquinol, econazole, fluconazole, flucytosine, griseofulvin, traconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, sulconazole, sulfanilamide, terbinafine, terconazole, undecylenic, voriconazole, and combinations thereof.

130. The lead system of claim 127, further comprising a second substrate and a bioactive agent supported by the second substrate.

131. The lead system of claim 127, wherein the lead system is configured to be at least partially implanted in a brain of a subject.

132. A method comprising:

forming an electrode of a medical lead system from a sintered metal so that the electrode is characterized by a plurality of pores, wherein the lead system comprises a lead body and the electrode is configured to connect to the lead body of the lead system;

introducing a bioactive agent to the electrode.

133. The method of claim 132, further comprising connecting the electrode to a lead body of the lead system.

134. The method of claim 132, further comprising releasing the bioactive agent from the electrode through the plurality of pores in the sintered metal.

135. The method of claim 132, wherein introducing the bioactive agent to the electrode comprises coating the pores of the sintered metal with the bioactive agent.

136. The method of claim 132, wherein the bioactive agent is selected from the group consisting of:

an antiproliferative agent, an antiepileptic agent, an antifungal agent, and combinations thereof.

137. The method of claim 136, wherein the bioactive agent is selected from the group consisting of:

bone morphogenic proteins, ciliary neurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel, cyclophosphamide, acetazolamide, carbamazepine, clonazepam, clorazepate, diazepam, divalproex, ethosuximide, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, mephobarbital, methsuximide, oxcarbazepine, phenacemide, phenobarbital, phenytoin, pregabalin, primidone, thiopental, tiagabine, topiramate, trimethadione, valproate, zonisamide, tetrodotoxin, amphotericin B, anidulafungin, butenafine, butoconazole, caspofungin, ciclopirox, clioquinol, econazole, fluconazole, flucytosine, griseofulvin, traconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, sulconazole, sulfanilamide, terbinafine, terconazole, undecylenic, voriconazole, and combinations thereof.