Coated implantable medical device

• US 20040047909A1
• Filed: 04/14/2003
• Published: 03/11/2004
• Est. Priority Date: 06/07/1995
• Status: Active Grant

• Current Assignee: Cook Medical Incorporated (Cook Group Incorporated)
• Original Assignee: Anthony O. Ragheb, Brian L. Bates, Neal E. Fearnot, Thomas A. Osborne, Thomas G. Kozma, William D. Voorhees III
• Inventors: Voorhees, William D. III, Bates, Brian L., Fearnot, Neal E., Kozma, Thomas G., Ragheb, Anthony O., Osborne, Thomas A.
• Granted Patent: US 7,445,628 B2
• Time in Patent Office: Days
• US Class Current: 424/471
• CPC Class Codes: A61F 2/24 Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61K 51/1282 Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/106 Inorganic materials other than carbon
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/088 Other specific inorganic materials not covered by A61L31/084 or A61L31/086
• 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: A61L 33/022 Metal or alloys
• CPC Class Codes: A61N 5/1002 Intraluminal radiation therapy
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C08L 65/04 : Polyxylenes

Abstract

Methods of making coated implantable medical devices are provided. The methods include positioning a first layer comprising a bioactive on at least a portion of a structure, and positioning at least one porous layer over the first layer. The at least one porous layer has a thickness adequate to provide a controlled release of the bioactive.

Claims

1. A method of making a medical device, comprising:

providing a structure comprising a base material;

positioning a bioactive on at least a portion of the base material;

positioning at least one porous layer over the bioactive, the at least one porous layer being of a thickness adequate to provide a controlled release of the bioactive.

2. The method of claim 1, wherein the bioactive comprises an antiproliferative agent.

3. The method of claim 2, wherein the bioactive comprises paclitaxel.

4. The method of claim 1, wherein the bioactive comprises an immunosuppressive agent.

5. The method of claim 4, wherein the immunosuppressive agent comprises sirolimus.

6. The method of claim 1, wherein the at least one porous layer comprises a polymer.

7. The method of claim 6, wherein the polymer comprises a polyimide, parylene, a parylene derivative, poly(ethylene oxide), poly(ethlyene glycol), poly(propylene oxide), silicone, or a polymer of methane, tetrafluoroethylene or tetramethyldisiloxane

8. The method of claim 1, wherein the at least one porous layer has a thickness of between about 5,000 and 250,000 Angstroms.

9. The method of claim 1, wherein the at least one porous layer has a thickness of between about 5,000 and 100,000 Angstroms.

10. The method of claim 1, wherein the at least one porous layer has a thickness of about 50,000 Angstroms.

11. The method of claim 1, wherein the structure comprises a vascular stent.

12. The method of claim 11, wherein the base material comprises stainless steel.

13. The method of claim 1, wherein the step of positioning a bioactive comprises positioning a bioactive at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

14. The method of claim 1, wherein the step of positioning a bioactive comprises positioning a bioactive at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure

15. A method of making a medical device, comprising:

providing a structure adapted for introduction into a patient and comprising a base material;

positioning a first layer comprising a bioactive on at least a portion of the base material; and

positioning at least one porous layer over the first layer, the at least one porous layer being of a thickness adequate to provide a controlled release of the bioactive.

16. The method of claim 15, wherein the bioactive comprises an antiproliferative agent.

17. The method of claim 16, wherein the bioactive comprises paclitaxel.

18. The method of claim 15, wherein the bioactive comprises an immunosuppressive agent.

19. The method of claim 18, wherein the immunosuppressive agent comprises sirolimus.

20. The method of claim 15, wherein the at least one porous layer comprises a polymer.

21. The method of claim 20, wherein the polymer comprises a polyimide, parylene, a parylene derivative, poly(ethylene oxide), poly(ethlyene glycol), poly(propylene oxide), silicone, or a polymer of methane, tetrafluoroethylene or tetramethyldisiloxane

22. The method of claim 15, wherein the at least one porous layer has a thickness of between about 5,000 to 250,000 Angstroms.

23. The method of claim 15, wherein the at least one porous layer has a thickness of between about 5,000 and 100,000 Angstroms.

24. The method of claim 15, wherein the at least one porous layer has a thickness of about 50,000 Angstroms.

25. The method of claim 15, wherein the structure comprises a vascular stent.

26. The method of claim 25, wherein the base material comprises stainless steel.

27. The method of claim 15, wherein the step of positioning a first layer comprises positioning a bioactive material on the structure with the bioactive at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

28. The method of claim 15, wherein the step of positioning a first layer comprises positioning a bioactive material on the structure with the bioactive at a concentration of between about 0.1 and 4 mg per cm2 of the gross surface area of the structure.

29. A method of making a bioactive-eluting stent, comprising:

providing a stent comprising a base material;

positioning a layer comprising a bioactive on at least a portion of the base material; and

positioning at least one porous layer over the layer comprising the bioactive, the at least one porous layer being of a thickness adequate to provide a controlled release of the bioactive.

30. The method of claim 29, wherein the bioactive comprises an antiproliferative agent.

31. The method of claim 30, wherein the bioactive comprises paclitaxel.

32. The method of claim 29, wherein the bioactive comprises an immunosuppressive agent.

33. The method of claim 32, wherein the immunosuppressive agent comprises sirolimus.

34. The method of claim 29, wherein the bioactive is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

35. The method of claim 29, wherein the bioactive is at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure.

36. A method of making a medical device, comprising:

providing a structure;

positioning a bioactive on at least a portion of the structure;

positioning by vapor deposition or plasma deposition at least one porous layer over the bioactive, the at least one porous layer comprising a polymer and having a thickness adequate to provide a controlled release of the bioactive.

37. The method of claim 36, wherein the bioactive comprises an antiproliferative agent.

38. The method of claim 37, wherein the bioactive comprises paclitaxel.

39. The method of claim 36, wherein the bioactive comprises an immunosuppressive agent.

40. The method of claim 39, wherein the immunosuppressive agent comprises sirolimus.

41. The method of claim 36, wherein the at least one porous layer has a thickness of between about 5,000 to 250,000 Angstroms.

42. The method of claim 36, wherein the at least one porous layer has a thickness of between about 5,000 and 100,000 Angstroms.

43. The method of claim 36, wherein the at least one porous layer has a thickness of about 50,000 Angstroms.

44. The method of claim 36, wherein the structure comprises a vascular stent.

45. The method of claim 44, wherein the stent includes a base material comprising stainless steel.

46. The method of claim 36, wherein the step of positioning a bioactive on the structure comprises positioning a bioactive on the structure at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

47. The method of claim 36, wherein the step of positioning a bioactive on the structure comprises positioning a bioactive on the structure at a concentration of between about 0.1 and 4 mg per cM² of the gross surface area of the structure.

48. A method of making an implantable medical device, the device including a structure adapted for introduction into a patient, and the structure being composed of a base material;

wherein the method comprises the steps of;

positioning at least one layer of a bioactive material comprising bioactive over the structure; and

positioning at least one porous layer by vapor deposition or plasma deposition over the at least one bioactive material layer, the at least one porous layer being composed of a polymer and being of a thickness adequate to provide a controlled release of the bioactive.

49. The method according to claim 48, wherein the step of positioning the at least one porous layer comprises polymerizing the at least one layer from a catalyst-free monomer vapor.

50. The method according to claim 48, wherein the step of positioning the at least one porous layer is carried out with a polyimide, parylene, a parylene derivative, poly(ethylene oxide), poly(ethlyene glycol), poly(propylene oxide), silicone, or a polymer of methane, tetrafluoroethylene or tetramethyldisiloxane.

51. The method according to claim 48, wherein the at least one porous layer is applied to a thickness of about 5,000 to 250,000 Angstroms.

52. The method of claim 48, wherein the at least one porous layer has a thickness of between about 5,000 and 100,000 Angstroms.

53. The method of claim 48, wherein the at least one porous layer has a thickness of about 50,000 Angstroms.

54. The method according to claim 48, wherein the step of positioning the at least one porous layer is carried out by sublimating and cracking di-p-xylylene or a derivative thereof to yield monomeric p-xylylene or a derivative thereof, and allowing the monomer so formed to simultaneously condense and polymerize over the bioactive material layer.

55. The method according to claim 54, wherein the sublimating and cracking step is carried out with dichloro-di-p-xylylene.

56. The method according to claim 48, wherein the step of positioning the at least one porous layer is carried out in the absence of a solvent or catalyst for the polymer.

57. The method according to claim 48, wherein the step of positioning the at least one layer of a bioactive material is carried out by applying over the structure a mixture of the bioactive material and a fluid, and removing the fluid prior to the step of positioning the at least one porous layer.

58. The method according to claim 57, wherein the fluid is volatile, and the fluid removing step is carried out by allowing the fluid to evaporate from the structure and bioactive material before the step of positioning the at least one porous layer.

59. The method according to claim 58, wherein the step of positioning the at least one layer of bioactive material is carried out with heparin, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, another dexamethasone derivative or another anti-inflammatory steroid as the bioactive, and ethyl alcohol as the volatile fluid.

60. The method according to claim 48, comprising the further step of positioning at least one additional coating layer between the structure and the at least one bioactive material layer.

61. The method according to claim 60, wherein the step of positioning the at least one additional coating layer is carried out so that the at least one additional coating layer is less porous than, but composed of the same polymer as, the at least one porous layer.

62. The method according to claim 61, wherein the step of positioning the at least one additional coating layer is carried out with polyimide, parylene or a parylene derivative, and the at least one coating layer is applied to a thickness of about 50,000 to 500,000 Angstroms.

63. The method of claim 61, wherein the at least one porous layer has a thickness of between about 5,000 and 100,000 Angstroms.

64. The method of claim 61, wherein the at least one porous layer has a thickness of about 50,000 Angstroms.

65. The method according to claim 48, wherein the method is carried out with a structure configured as a vascular stent.

66. The method according to claim 48, wherein the method is carried out with a structure configured as at least one of:

a catheter, a wire guide, a cannula, a stent, a vascular or other graft, a cardiac pacemaker lead or lead tip, a cardiac defibrillator lead or lead tip, a heart valve, a suture, or a needle;

an angioplasty device or portion thereof;

a pacemaker or portion thereof;

an orthopedic device, appliance, implant or replacement, or portion thereof;

or a portion of any of these.

67. The method according to claim 48, wherein the method is carried out with a structure whose base material is biocompatible.

68. The method according to claim 67, wherein the method is carried out with a structure whose base material includes at least one of:

stainless steel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium, silver, tungsten, or another biocompatible metal, or alloys of any of these;

carbon or carbon fiber;

cellulose acetate, cellulose nitrate, silicone, polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or another biocompatible polymeric material, or mixtures or copolymers of these;

polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxy-butyrate valerate or another biodegradable polymer, or mixtures or copolymers of these;

a protein, an extracellular matrix component, collagen, fibrin or another biologic agent;

or a mixture of any of these.

69. The method according to claim 48, wherein the step of positioning the at least one bioactive material layer is carried out with a bioactive material which includes at least one of:

heparin or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent, or mixtures thereof;

urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof;

a fibrinolytic agent;

a vasospasm inhibitor;

a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter or another vasodilator;

an antimicrobial agent or antibiotic;

aspirin, ticlopdine, a glycoprotein IIb/IIIa inhibitor or another inhibitor of surface glycoprotein receptors, or another antiplatelet agent;

colchicine or another antimitotic, or another microtubule inhibitor, dimethylsulfoxide (DMSO), a retinoid or another antisecretory agent;

cytochalasin or another actin inhibitor;

or a remodelling inhibitor;

deoxyribonucleic acid, an antisense nucleotide or another agent for molecular genetic intervention;

methotrexate or another antimetabolite or antiproliferative agent;

an anti-cancer chemotherapeutic agent;

dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or another dexamethasone derivative, or another anti-inflammatory steroid or nonsteroidal antiinflammatory agent;

cyclosporin or another immunosuppressive agent;

trapidal (a PDGF antagonist), angiopeptin (a growth hormone antagonist), an anti-growth factor antibody, or another growth factor antagonist;

dopamine, bromocriptine mesylate, pergolide mesylate or another dopamine agonist;

⁶⁰Co, ¹⁹²Ir, ³²P, ¹¹¹In, ⁹⁰Y, ^99mTc or another radiotherapeutic agent;

iodine-containing compounds, barium-containing compounds, gold, tantalum, platinum, tungsten or another heavy metal functioning as a radiopaque agent;

a peptide, a protein, an enzyme, an extracellular matrix component, a cellular component or another biologic agent;

captopril, enalapril or another angiotensin converting enzyme (ACE) inhibitor;

ascorbic acid, alphatocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid (lasaroid) or another free radical scavenger, iron chelator or antioxidant;

a ¹⁴C-, ³H-, ¹³¹I-, ³²P- or ³⁶S-radiolabelled form or other radiolabelled form of any of the foregoing;

or a mixture of any of these.

70. The method according to claim 48, wherein the step of positioning the at least one layer of bioactive material is carried out so that the at least one layer contains between about 1 to 4 mg of the bioactive per cm² of the gross surface area of the structure.

71. The method according to claim 48, comprising positioning at least two layers of different bioactive materials over the structure.

72. The method according to claim 71, further comprising positioning an additional porous layer of the polymer between each of the at least two layers of different bioactive materials.

73. The method according to claim 71, wherein the method is carried out with two different bioactives having different solubilities, and wherein the method comprises positioning the layer containing the less soluble bioactive above the layer containing the more soluble bioactive.

74. The method according to claim 73, further comprising positioning an additional porous layer of the polymer between each of the at least two layers of different bioactive materials.

75. The method according to claim 48, comprising the further step of securing the at least one porous layer to the base material of the structure by a connector.

76. The method according to claim 48, comprising the further step of surface processing the base material before positioning the at least one bioactive material layer over the structure.

77. The method according to claim 60, comprising the further step of surface processing the at least one additional coating layer before positioning the at least one bioactive material layer over the structure.

78. The method according to claim 72, comprising the further step of surface processing the additional porous layer before positioning the upper of the at least two bioactive material layers over the structure.

79. The method according to claim 74, comprising the further step of surface processing the additional porous layer before positioning the upper of the at least two bioactive material layers over the structure.

80. A method of making a medical device, comprising:

providing a structure;

positioning a first layer comprising a bioactive on at least a portion of the structure;

applying a polymer solution over at least a portion of the first layer to form at least one porous layer over the first layer, the at least one porous layer being of a thickness adequate to provide a controlled release of the bioactive.

81. The method of claim 80, wherein the bioactive comprises an antiproliferative.

82. The method of claim 81, wherein the bioactive comprises paclitaxel.

83. The method of claim 80, wherein the bioactive comprises an immunosuppressive agent.

84. The method of claim 83, wherein the immunosuppressive agent comprises sirolimus.

85. The method of claim 80, wherein the bioactive is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

86. The method of claim 80, wherein the bioactive is at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure.

87. The method of claim 80, wherein the structure comprises a vascular stent.

88. The method of claim 87, wherein the stent includes a base material comprising stainless steel.

89. The method of claim wherein the step of applying a polymer solution comprises one of dipping, rolling, brushing, spraying, and electrostatic deposition of the solution.

90. A method of making a bioactive-eluting stent, comprising positioning a first layer comprising paclitaxel on at least a portion of a stent and positioning at least one porous layer over the first layer in a thickness adequate to provide a controlled release of the paclitaxel.

91. The method of claim 90, wherein the paclitaxel is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

92. The method of claim 90, wherein the paclitaxel is at a concentration of between about 1 and 4 mg per cm² of the gross surface area of the structure.

93. A method of making a bioactive-eluting stent, comprising positioning a first layer comprising an immunosuppressive agent on at least a portion of a stent and positioning at least one porous layer over the first layer in a thickness adequate to provide a controlled release of the immunosuppressive agent.

94. The method of claim 93, wherein the immunosuppressive agent is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

95. The method of claim 93, wherein the immunosuppressive agent is at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure.

96. The method of claim 93, wherein the immunosuppressive agent comprises sirolimus.

97. A method of making a bioactive-eluting stent, comprising positioning a first layer comprising a bioactive on at least a portion of a stent and applying a polymer over the first layer until the polymer has a thickness adequate to provide a controlled release of the bioactive.

98. The method of claim 97, wherein the bioactive comprises an antiproliferative agent.

99. The method of claim 98, wherein the bioactive comprises paclitaxel.

100. The method of claim 97, wherein the bioactive comprises an immunosuppressive agent.

101. The method of claim 100, wherein the immunosuppressive agent comprises sirolimus.

102. The method of claim 97, wherein the bioactive is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

103. The method of claim 97, wherein the bioactive is at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure.

104. A method of making a bioactive eluting stent, comprising sequentially applying a bioactive-containing layer and a porous layer of a thickness adequate to provide a controlled release of the bioactive to a stent.

105. The method of claim 104, wherein the bioactive comprises an antiproliferative agent.

106. The method of claim 105, wherein the bioactive comprises paclitaxel.

107. The method of claim 104, wherein the bioactive comprises an immunosuppressive agent.

108. The method of claim 107, wherein the immunosuppressive agent comprises sirolimus.

109. A method of treating a human or veterinary patient, comprising implanting a medical device at a point of treatment, the medical device comprising a surface, a first layer comprising a bioactive posited on at least a portion of the surface, and a porous layer overlaying the first layer and having a thickness adequate to provide a controlled release of the bioactive.

110. The method of claim 109, wherein the bioactive comprises an antiproliferative agent.

111. The method of claim 110, wherein the bioactive comprises paclitaxel.

112. The method of claim 109, wherein the bioactive comprises an immunosuppressive agent.

113. The method of claim 112, wherein the immunosuppressive agent comprises sirolimus.

114. The method of claim 109, wherein the medical device comprises a vascular stent.

115. The method of claim 109, wherein the bioactive is at a concentration of between about 0.01 and 10 mg bioactive per cm of the gross surface area of the structure.

116. The method of claim 109, wherein the bioactive is at a concentration of between about. 1 and 4 mg bioactive per cm² of the gross surface area of the structure.

117. A method of inhibiting restenosis in a blood vessel, comprising deploying a medical device in the vessel, the medical device comprising a surface, a first layer comprising a bioactive and posited on at least a portion of the surface, and a porous layer overlaying the first layer and having a thickness adequate to provide a controlled release of the bioactive over a period of between about four and six months.

118. The method of claim 117, wherein the bioactive comprises an antiproliferative.

119. The method of claim 118, wherein the bioactive comprises paclitaxel.

120. The method of claim 117, wherein the bioactive comprises an immunosuppressive agent.

121. The method of claim 120, wherein the immunosuppressive agent comprises sirolimus.

122. The method of claim 117, wherein the immunosuppressive agent is at a concentration of between about 0.01 and 10 mg per cm² of the gross surface area of the structure.

123. The method of claim 117, wherein the immunosuppressive agent is at a concentration of between about 0.1 and 4 mg per cm² of the gross surface area of the structure.