Medical devices having porous layers and methods for making the same

• US 20050070989A1
• Filed: 08/13/2004
• Published: 03/31/2005
• Est. Priority Date: 11/13/2002
• Status: Abandoned Application

• Current Assignee: Medtronic Vascular, Inc. (Medtronic Plc), University of Virginia Patent Foundation (University of Virginia)
• Original Assignee: Medtronic Vascular, Inc. (Medtronic Plc)
• Inventors: Reed, Michael, Lye, Whye-Kei, Looi, Kareen, Wamhoff, Brian, Hudson, Matthew, Owens, Gary
• Application Number:
  US10/918,853
• Publication Number:
  US 20050070989A1
• Time in Patent Office: Days
• US Class Current: 623/1.400
• CPC Class Codes: A61F 2/86 Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
• 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 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 31/082 Inorganic 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

The present invention relates generally to medical devices with therapy eluting components and methods for making same. More specifically, the invention relates to implantable medical devices having at least one porous layer, and methods for making such devices, and loading such devices with therapeutic agents. A mixture or alloy is placed on the surface of a medical device, then one component of the mixture or alloy is generally removed without generally removing the other components of the mixture or alloy.

Claims

1. A stent for insertion into a body structure, comprising:

a tubular member having;

a first end and a second end,

a lumen extending along a longitudinal axis between the first end and the second end,

an outer surface,

an inner luminal surface; and

at least one porous layer, the porous layer comprising an interstitial structure and an interstitial space;

wherein the interstitial space is generally configured by the removal of at least one sacrificial material from a mixture comprising at least one sacrificial material with one or more structural materials that comprise the interstitial structure of the porous layer; and

wherein the porous layer is adapted to receive and release at least one therapeutic agent.

2. The stent of claim 1, further comprising a therapeutic agent within at least a portion of the interstitial space.

3. The stent of claim 1, wherein the interstitial space is generally configured by a dealloying process.

4. The stent of claim 1, wherein at least a portion of the porous layer extends between the outer surface and the luminal surface.

5. The stent of claim 1, wherein the average pore size of the porous layer is within the range of about 5 nm to about 1000 nm.

6. The stent of claim 5, wherein the average pore size of the porous layer is within the range of about 5 nm to about 100 nm.

7. The stent of claim 6, wherein the average pore size of the porous layer is within the range of about 5 nm to about 10 nm.

8. The stent of claim 1, wherein the structural material is gold and the average pore size of the porous layer is within the range of about 5 nm to about 500 nm.

9. The stent of claim 1, wherein the average thickness of the porous layer is within the range of about 2 nm to about 5 mm.

10. The stent of claim 9, wherein the average thickness of the porous layer is within the range of about 5 nm to about 5 μ

m.

11. The stent of claim 10, wherein the average thickness of the porous layer is within the range of about 5 nm to about 50 nm.

12. The stent of claim 10, wherein the average thickness of the porous layer is about 10 nm.

13. The stent of claim 1, wherein the interstitial volume per volume of porous layer is between about 10 percent and about 90 percent.

14. The stent of claim 1, wherein the porous layer has a substantially non-uniform interstitial volume per volume of porous layer.

15. The stent of claim 14, wherein the non-uniformity of the interstitial volume per volume of porous layer is graded.

16. The stent of claim 14, wherein the non-uniformity of the interstitial volume per volume of porous layer is abrupt.

17. The stent of claim 1, wherein the porous layer has a non-uniform pore size.

18. The stent of claim 15, comprising a first zone having a first average pore size and a second zone having a second average pore size.

19. The stent of claim 18, wherein the pore size transitions gradually between the first zone and the second zone.

20. The stent of claim 1, wherein the porous layer has a non-uniform layer thickness.

21. The stent of claim 20, comprising a first thickness at a first point, and a second thickness at a second point.

22. The stent of claim 21, wherein the layer thickness transitions gradually between the first point and the second point.

23. The stent of claim 15, wherein the porous layer has a substantially non-uniform pore size along the longitudinal axis of the tubular member.

24. The stent of claim 15, wherein the porous layer has a substantially non-uniform pore size circumferentially around the tubular member.

25. The stent of claim 20, wherein the porous layer has a non-uniform layer thickness along the longitudinal axis of the tubular member.

26. The stent of claim 20, wherein the porous layer has a non-uniform layer thickness around the circumference of the tubular member.

27. The stent of claim 14, wherein the interstitial volume per volume of porous layer is non-uniform along the longitudinal axis of the tubular member.

28. The stent of claim 14, wherein the interstitial volume per volume of porous layer is non-uniform around the circumference of the tubular member.

29. The stent of claim 1, wherein

at least a portion of the outer surface of the tubular member comprises a first porous layer;

and

at least a portion of the inner luminal surface of the tubular member comprises a second porous layer.

30. The stent of claim 29, wherein at least a portion of the interstitial space of the first porous layer is filled with a therapeutic agent selected from the group comprising:

actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus.

31. The stent of claim 29, wherein at least a portion of the interstitial space of the second porous layer is filled with a therapeutic agent selected from the group comprising:

actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, antithrombotic agents, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine, and ACE inhibitors.

32. The stent of claim 1, further comprising at least one therapeutic agent that is at least partially contained within the interstitial space of the porous layer, the therapeutic agent selected from a group comprising:

actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine, and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, an anti-restenosis agent, an anti-thrombogenic agent, an antibiotic, an anti-platelet agent, an anti-clotting agent, an anti-inflammatory agent, an anti-neoplastic agent, a chelating agent, penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments, antibodies, live cells, therapeutic drug delivery microspheres or microbeads, gene therapy agents, viral vectors and plasmid DNA vectors.

33. The stent of claim 1, wherein the porous layer further comprises at least one elution rate altering material within or about at least a portion of the interstitial space of the porous layer.

34. The stent of claim 33, further comprising at least one therapeutic agent within at least a portion of the interstitial space.

35. The stent of claim 34, wherein the elution rate altering material is distinct from the therapeutic agent.

36. The stent of claim 34, wherein the elution rate altering material is mixed with the therapeutic agent.

37. The stent of claim 33, wherein the elution rate altering material comprises a diffusion barrier.

38. The stent of claim 33, wherein the elution rate altering material comprises a biodegradeable material.

39. The stent of claim 33, wherein the elution rate altering material comprises a polymer or hydrogel.

40. The stent of claim 33, wherein the porous layer further comprises a first elution rate altering layer, a first therapeutic agent, a second elution rate altering layer, and a second therapeutic agent;

wherein the first elution rate altering layer comprises a first elution rate altering material and the second elution rate altering layer comprises a second elution rate altering material.

41. The stent of claim 40, wherein the first elution rate altering material is different from the second elution rate altering material.

42. The stent of claim 40, wherein the first therapeutic agent is different from the second therapeutic agent.

43. The stent of claim 40, wherein the first elution rate altering layer has an average thickness different from the average thickness of the second elution rate altering layer.

44. The stent of claim 1, wherein at least one sacrificial material is nonmetallic.

45. The stent of claim 44, wherein at least one sacrificial material is selected from the group consisting of:

glass, polystyrene, plastics, alumina, salts, proteins, carbohydrates, and oils.

46. The stent of claim 1, wherein at least one structural material is nonmetallic.

47. The stent of claim 46, wherein at least one structural material is selected from a list comprising silicon dioxide, silicon nitride, silicon, polystyrene, sodium chloride, and polyethylene.

48. The stent of claim 1, comprising a first porous layer and a second porous layer, wherein at least a portion of the first porous layer is positioned between at least a portion of the second porous layer and a portion of the tubular member.

49. The stent of claim 1, wherein the interstitial space is configured generally by the removal of at least two sacrificial materials from a mixture comprising at least two sacrificial materials abd at least one structural material, the structural material forming at least a portion of the interstitial structure of the porous layer.

50. The stent of claim 1, wherein the interstitial structure comprises at least one material selected from the group consisting of:

gold, silver, nitinol, steel, chromium, iron, nickel, copper, aluminum, titanium, tantalum, cobalt, tungsten, palladium, vanadium, platinum, niobium, a salt, and an oxide particle.

51. The stent of claim 1, wherein the interstitial space is configured by removing at least one sacrificial material with a dealloying process.

52. The stent of claim 1, wherein the interstitial space is configured by removing at least one sacrificial material with high pressure evaporation.

53. The stent of claim 2, wherein the therapeutic agent is loaded onto the stent through exposure to a solution containing the therapeutic agent.

54. The stent of claim 53, wherein the therapeutic agent is loaded onto the stent in an environment less than 760 torr.

55. The stent of claim 53, wherein the solution comprises a solvent.

56. The stent of claim 55, wherein the solvent has a high solubility product for the therapeutic agent but a vapor pressure less than water.

57. The stent of claim 2, wherein the therapeutic agent is loaded onto the stent while the solvent resorbs at least some of the gaseous material within the interstitial space.

58. The stent of claim 53, wherein the therapeutic agent is loaded onto the stent in a supercooled environment.

59. A therapy-eluting medical device, comprising:

at least one component of a medical device having at least one therapy-eluting surface comprising an interstitial structure and an interstitial space, wherein the interstitial space is configured generally by the removal of at least a portion of one sacrificial material from a mixture comprising at least one sacrificial material and one or more structural materials that comprise the interstitial structure of the porous layer; and

wherein the therapy-eluting surface is adapted to receive and release at least one therapeutic agent.

60. The medical device of claim 59, wherein the medical device is a stent.

61. The medical device of claim 59, wherein the medical device is a vascular graft.

62. The medical device of claim 59, wherein the medical device is an orthopedic device.

63. The medical device of claim 59, wherein the medical device is an implantable sensor housing.

64. The medical device of claim 59, wherein the medical device is an artificial valve.

65. The medical device of claim 59, wherein the medical device is a contraceptive device.

66. The medical device of claim 65, wherein the contraceptive device is an inter-uterine device.

67. The medical device of claim 65, wherein the contraceptive device is subcutaneous hormonal implant.

68. The medical device of claim 59, wherein the medical device is a wire coil.

69. The medical device of claim 68, wherein the medical device is a neural coil.

70. The medical device of claim 59, wherein the medical device is a vascular coil for treatment of an aneurysm.

71. The medical device of claim 59, wherein the medical device is a suture.

72. The medical device of claim 59, wherein the medical device is a staple.

73. The medical device of claim 59, wherein the medical device is a guidewire.

74. The medical device of claim 59, wherein the medical device is a catheter.

75. A therapy-eluting medical device, comprising:

at least one component of a medical device having at least one porous surface comprising an interstitial structure and an interstitial space, wherein the interstitial space is configured generally by the removal of at least a portion of one sacrificial material from a mixture comprising at least one sacrificial material and one or more structural materials that comprise the interstitial structure of the porous layer.

76. The medical device of claim 75, wherein the porous layer is adapted to absorb a range of substances.

77. The medical device of claim 75, wherein the porous layer is adapted to facilitate tissue ingrowth over the porous layer.

78. A method for manufacturing a medical device with at least one non-polymeric porous layer, comprising the steps of:

providing at least a component of a medical device having at least one surface; and

depositing a layer of a material onto at least a portion of the surface;

the layer of material comprising at least one sacrificial component and at least one structural component and at least one component is not a polymer or therapeutic agent.

79. The method of claim 78, wherein the depositing step comprises high pressure sputtering of the material.

80. The method of claim 78, wherein the depositing step comprises directed vapor deposition of the material.

81. The method of claim 78, wherein the depositing step comprises sintering of the material.

82. The method of claim 81, wherein the material of the depositing step comprises a powder.

83. The method of claim 81, wherein the material of the depositing step comprises beads.

84. The method of claim 78, further comprising the step of:

removing at least a portion of at least one sacrificial component to form an interstitial space.

85. The method of claim 84, wherein the removing step comprises applying a solvent to at least a portion of at least one sacrificial component.

86. The method of claim 85, wherein the removing step comprises applying a solvent/therapeutic agent combination to at last a portion of at least one sacrificial component.

87. The method of claim 78, further comprising applying a magnetic field to at least a portion of the component of the medical device to at least partially orient at least one component of the layer of material.

88. The method of claim 87, further comprising varying the intensity or direction of the magnetic field during the depositing step.

89. The method of claim 78, further comprising the step of removing at least one sacrificial material from the layer of mixed materials to form a porous layer.

90. The method of claim 78, wherein the porous layer has a metallic structure.

91. A method of loading a porous medical device with a therapeutic agent, comprising the steps of:

providing at least a component of a medical device having a dealloyed porous zone, the dealloyed porous zone comprising an interstitial structure and an interstitial space; and

filling at least a portion of the interstitial space with at least one therapeutic agent.

92. The method of claim 91, wherein the filling step is performed by placing at least a portion of the interstitial space of the medical device into a solution containing the therapeutic agent.

93. The method of claim 91, wherein the filling step is performed by spraying a solution containing the therapeutic agent onto at least a portion of the interstitial space of the medical device.

94. The method of claim 91, wherein the filling step is performed by placing at least a portion the interstitial space of the medical device into a flow of a solution containing the therapeutic agent.

95. The method of claim 91, wherein the filling step is performed by placing at least a portion the interstitial space of the medical device into a loading vessel and filling the vessel with a solution containing the therapeutic agent.

96. The method of claim 91, further comprising the step of:

preparing the interstitial space for filling with the therapeutic agent.

97. The method of claim 96, wherein the preparing step comprises evacuating at least a portion of any gaseous material from at least a portion of the interstitial space.

98. The method of claim 97, wherein the filling step is performed in a subatmospheric environment.

99. The method of claim 98, wherein the filling step is performed in a vacuum environment.

100. The method of claim 97, wherein the preparing step comprises evacuating gaseous material from at least a portion of the interstitial space by exposing at least a portion of the interstitial space to subatmospheric pressure.

101. The method of claim 96, wherein the preparing step comprises applying an electrical charge to the interstitial structure.

102. The method of claim 96, wherein the preparing step comprises exposing at least a portion of the interstitial space to a gaseous material.

103. The method of claim 102, wherein the gaseous material comprises a solvent-soluble gaseous material to facilitate removal of trapped gas.

104. The method of claim 103, wherein the therapeutic agent of the filling step is provided in a gaseous material-soluble solvent.

105. The method of claim 104, further comprising reabsorbing at least a portion of the gaseous material into the gaseous material-soluble solvent.

106. The method of claim 105, wherein the reabsorbing step is performed under subatmospheric pressure.

107. The method of claim 91, wherein the therapeutic agent comprises a therapeutic substance and a carrier.

108. The method of claim 107, further comprising precipitating the therapeutic substance in the interstitial space.

109. The method of claim 108, wherein the precipitating step is performed by removal of at least a portion of the carrier from the interstitial space.

110. The method of claim 107, wherein the carrier comprises a substance selected from the group consisting of:

an alcohol, water, a ketone, a lipid, and an ester.

111. The method of claim 107, wherein the carrier comprises a solvent.

112. The method of claim 111, wherein the solvent is selected from a group comprising de-ionized water, ethanol, methanol, DMSO, acetone and chloroform.

113. The method of claim 111, wherein the solvent has a sufficient solubility product for the therapeutic agent but a vapor pressure less than water.

114. The method of claim 113, wherein the filling step is performed at a vapor pressure generally between the vapor pressure of the solvent but less than water.

115. The method of claim 114, further comprising exposing at least a portion of the interstitial space of the medical device to an aqueous solution with a low solubility product for the therapeutic agent.

116. The method of claim 115, wherein the exposing step is performed after the filling step.

117. The method of claim 91, further comprising the step of:

exposing the device to a below ambient pressure environment for the filling step.

118. The method of claim 117, wherein the below ambient pressure environment is below about 760 torr.

119. The method of claim 118, wherein the below ambient pressure environment is below about 380 torr.

120. The method of claim 119, wherein the below ambient pressure environment is below about 190 torr.

121. The method of claim 120, wherein the below ambient pressure environment is below about 100 torr.

122. The method of claim 121, wherein the below ambient pressure environment is below about 60 torr.

123. The method of claim 122, wherein the below ambient pressure environment is below about 30 torr.

124. The method of claim 117, further comprising the step of supercooling the environment to reduce the vapor pressure of the solvent used for loading the therapeutic agent.

125. The method of claim 91, further comprising the step of:

exposing the device to an above ambient pressure environment for at least a portion of the filling step.

126. The method of claim 91, further comprising the step of:

loading a propellant into the interstitial space.

127. The method of claim 126, wherein the loading step is performed before the filling step.

128. The method of claim 91, further comprising the step of:

determining the amount of therapeutic agent filling the interstitial space.

129. The method of claim 91, further comprising the step of:

changing the amount of therapeutic agent filling the interstitial space or on the surface of the nanoporous coating.

130. The method of claim 91, wherein the filling step is performed at the point of use.

131. The method of claim 91, wherein the filling step is performed at the point of manufacture.

146. The method of claim 91, further comprising removing at least a portion of any surface deposited therapeutic agent.

147. The method of claim 91, further comprising batch washing the component with a solvent with known solubility for the therapeutic agent.

148. The method of claim 147, wherein the batch washing step is performed with a defined volume of solvent.

149. The method of claim 91, further comprising altering the amount of therapeutic agent by exposing the component to controlled air streams or blasts.

150. The method of claim 149, wherein the altering step is performed using high velocity air streams or blasts.

151. The method of claim 91, further comprising altering the amount of therapeutic agent by controlled mechanical wiping.

152. The method of claim 91, further comprising altering the amount of therapeutic agent by washing with one or more solvents with known solubilities for the therapeutic agent or agents.

153. The method of claim 152, wherein the washing step is performed with a defined volume of at least one solvent.

132. A method of treating a patient, comprising the steps of:

providing a medical device with a nanoporous component loaded with a therapeutic agent;

placing the medical device at a treatment site; and

releasing at least a portion of the therapeutic agent from the porous component under active pressure.

133. The method of claim 132, wherein the active pressure is generated by a propellant loaded in the porous component.

134. The method of claim 132, wherein the releasing step of at least a portion of the therapeutic agent is performed by the therapeutic agent loaded into the porous component at a pressure higher than physiologic pressure.

135. The method of claim 134, wherein the releasing step of at least a portion of the therapeutic agent is performed by the therapeutic agent loaded into the porous component at a pressure of at least 180 mm Hg.

136. The method of claim 135, wherein the releasing of at least a portion of the therapeutic agent is performed by the therapeutic agent loaded into the porous component at a pressure of at least 250 mm Hg.

137. The method of claim 135, wherein the releasing of at least a portion of the therapeutic agent is performed by the therapeutic agent loaded into the porous component at a pressure of at least 300 mm Hg.

138. A method of treating a patient, comprising the steps of:

providing a medical device with a porous component loaded with a prodrug;

placing the medical device at a treatment site;

releasing at least a portion of the prodrug from the porous component; and

reacting the prodrug generally within the treatment site to form an active drug.

139. The method of claim 138, wherein the treatment site is a coronary artery.

140. The method of claim 138, wherein the treatment site is a portion of the biliary tree.

141. The method of claim 138, wherein the reacting step is performed by white blood cells.

142. The method of claim 138, wherein the reacting step is performed by myeloperoxidase released by white blood cells.

143. The method of claim 138, wherein the reacting step is performed by macrophages.

144. The method of claim 139, wherein the reacting step is performed by renin in the vascular wall.

145. The method of claim 138, wherein the reacting step is performed with a reactant loaded into the medical device.

154. A device for loading porous medical devices with a therapeutic agent, comprising:

a vacuum chamber;

a vacuum pump attached to the vacuum chamber,

a therapeutic reagent reservoir;

a flow controller attached to the reservoir; and

a porous device holder within the vacuum chamber.

155. The device of claim 154, wherein the flow controller comprises a controllable pump generally between the therapeutic reagent housing and the porous device holder.

156. The device of claim 154, wherein the flow controller comprises a hinge generally attached to one end of the therapeutic reagent reservoir and a releasable reservoir support generally attached to the other end of the therapeutic reagent housing.

157. The device of claim 154, further comprising a remote control for manipulating the flow controller.