Use of Plasma in Formation of Biodegradable Stent Coating

• US 20110093056A1
• Filed: 12/23/2010
• Published: 04/21/2011
• Est. Priority Date: 06/02/2006
• Status: Abandoned Application

• Current Assignee: JW Medical Systems Ltd
• Original Assignee: XTENT, Inc.
• Inventors: Ruane, Patrick H., Kimura, Torsten, Lang, Eric A., Kaplan, Stephen L.
• Application Number:
  US12/977,472
• Publication Number:
  US 20110093056A1
• Time in Patent Office: Days
• US Class Current: 623/1.11
• 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 2002/826 more than one stent being applied sequentially
• CPC Class Codes: A61F 2002/9155 Adjacent bands being connected to each other
• CPC Class Codes: A61F 2002/91558 connected peak to peak
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0013 Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2300/606 Coatings
• 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: B05B 13/0228 the movement of the objects being rotative B05B13/0242 takes precedence
• CPC Class Codes: B05B 13/0442 Installation or apparatus for applying liquid or other fluent material to separate articles rotated during spraying operation
• CPC Class Codes: Y10T 428/1352 Polymer or resin containing [i.e., natural or synthetic]

Abstract

Metallic stents are treated with a gaseous species in a plasma state under conditions causing the species to polymerize and to be deposited in polymerized form on the metallic stent surface prior to the application of a drug-polymer mixture, which is done by conventional non-plasma deposition methods. The drug-polymer mixture once applied forms a coating on the stent surface that releases the drug in a time-release manner and gradually erodes, leaving only the underlying plasma-deposited polymer. In certain cases, the plasma-deposited polymer itself erodes or dissolves into the physiological medium over an extended period of time, leaving only the metallic stent. While the various polymers and drug remain on the stent, the plasma-deposited polymer enhances the adhesion of the drug-polymer anchor coating and maintains the coating intact upon exposure to the mechanical stresses encountered during stent deployment.

Claims

1. A method for the manufacture of an intraluminal device bearing a therapeutic agent releasable from the device in a time-controlled manner, the method comprising:

exposing a metallic substrate to a gaseous plasma form of a substance that polymerizes in the plasma form under conditions causing the substance to form a polymer anchor coating of about 500 Å

in thickness or less on the substrate; and

depositing over the polymer anchor coating a layer containing the therapeutic agent wherein substantially all of the therapeutic agent is releasable into a physiological environment gradually over a period ranging from about one hour up to about six months.

2. A method as in claim 1, wherein the polymer anchor coating is adapted to withstand significant cracking during expansion of the intraluminal device.

3. A method as in claim 1, wherein the polymer anchor coating remains coupled to the intraluminal device during expansion thereof, without substantially separating therefrom.

4. A method as in claim 1, wherein a physiological fluid dissolves the therapeutic agent.

5. A method as in claim 4, wherein the physiological fluid comprises blood or cytoplasm.

6. A method as in claim 1, wherein the step of depositing results in swelling of the polymer anchor coating thereby enhancing diffusion of the therapeutic agent into the polymer anchor coating.

7. A method as in claim 1, wherein the metallic substrate comprises a material selected from the group consisting of stainless steel, nickel-titanium alloys and cobalt-chromium alloys.

8. A method as in claim 1, wherein the substance is either in gaseous form under ambient conditions or the substance can be volatilized.

9. A method as in claim 8, wherein the substance comprises a material selected from the group consisting of allyl substituted compounds, acrylic acids, methacrylic acids, acrylates, methacrylates, ethylene glycol, organosilicones, thiophenes, vinyl benzene, vinyl pyrrolidinone, and methane.

10. A method as in claim 1, wherein the polymer anchor coating is continuous over substantially all of a surface of the metallic substrate.

11. A method as in claim 1, wherein the step of exposing the metallic substrate comprises exposing the metallic substrate to a inert diluent noble gas in the presence of the substance to be polymerized.

12. A method as in claim 1, further comprising masking a portion of the substrate so as to selectively apply the polymer anchor coating to the substrate.

13. A method as in claim 1, further comprising controlling the degree of polymerization of the substance.

14. A method as in claim 13, wherein controlling comprises a step selected from the group consisting of limiting power level, limiting exposure time and applying power in a pulsewise manner.

15. A method as in claim 1, further comprising controlling the degree of cross-linking of the substance.

16. A method as in claim 15, wherein controlling comprises a step selected from the group consisting of limiting power level, limiting exposure time and applying power in a pulsewise manner.

17. A method as in claim 1, further comprising cleaning of a surface of the substrate.

18. A method as in claim 1, wherein the therapeutic agent comprises at least one of antibiotics, thrombolytics, anti-platelet agents, anti-inflammatories, cytotoxic agents, anti-proliferative agents, vasodilators, gene therapy agents, radioactive agents, immunosuppressants, chemotherapeutics, endothelial cell attractors, endothelial cell promoters, stem cells, hormones, smooth muscle relaxants, mTOR inhibitors and combinations thereof.

19. A method as in claim 1, wherein the step of depositing comprises one of dipping, spraying, brush coating, syringe deposition, chemical vapor deposition or plasma deposition of the layer of the therapeutic agent over the polymer anchor coating.

20. A method as in claim 1, wherein the step of depositing comprises rotating a mandrel with the intraluminal device disposed thereon.

21. A method as in claim 1, wherein the therapeutic agent is dispersed in a polymeric matrix positioned over the polymer anchor coating.

22. A method as in claim 21, wherein the polymeric matrix comprises a first polymer layer disposed over the therapeutic agent.

23. A method as in claim 22, wherein the polymeric matrix is adapted to control release rate of the therapeutic agent from the layer containing the therapeutic agent.

24. A method as in claim 22, wherein the polymeric matrix further comprises a second therapeutic agent disposed over the first polymer layer.

25. A method as in claim 24, wherein the polymeric matrix further comprises a second polymer layer disposed over the second therapeutic agent.

26. A method as in claim 21, wherein the polymeric matrix is a different polymer than the polymer anchor coating.

27. A method as in claim 21, wherein the polymeric matrix biodegrades from the polymer anchor coating over a period not exceeding twenty-four months.

28. A method as in claim 21, wherein the polymeric matrix diffuses into the polymer anchor coating.

29. A method as in claim 21, wherein the polymeric matrix bonds to the polymer anchor coating.

30. A method as in claim 21, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the physiological fluid into the polymeric matrix thereby dissolving the therapeutic agent.

31. A method as in claim 30, wherein the physiological fluid comprises blood or cytoplasm.

32. A method as in claim 21, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the physiological fluid into the polymeric matrix, thereby promoting bioerosion of the matrix.

33. A method as in claim 32, wherein the physiological fluid comprises blood or cytoplasm.

34. A method as in claim 21, wherein the polymer matrix comprises a material selected from the group consisting of polyhydroxyalkanoates, polyalphahydroxy acids, polysaccharides, proteins, hydrogels, lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohols, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride, acrylates, cyanoacrylates, methacrylates and poly(glycerol-sebacate).

35. A method as in claim 21, further comprising varying porosity of the polymer anchor coating in order to control blending of the polymer matrix with the polymer anchor coating thereby controlling release rate of the therapeutic agent from the polymer matrix.

36. A method for the manufacture of an intraluminal device bearing a therapeutic agent releasable from the device in a time-controlled manner, the method comprising:

exposing a metallic substrate to a gaseous plasma form of a substance that polymerizes in the plasma form under conditions causing the substance to form a polymer anchor coating on the substrate; and

depositing over the polymer anchor coating a layer containing the therapeutic agent in a polymer matrix that releases substantially all of the therapeutic agent into a physiological environment gradually over a period ranging from about one hour up to about six months,

and wherein following release of the therapeutic agent, any polymer remaining on the substrate is about 500 Å

or less in thickness.

37. A method as in claim 36, wherein the polymer anchor coating is adapted to withstand significant cracking during expansion of the intraluminal device.

38. A method as in claim 36, wherein the polymer anchor coating remains coupled to the intraluminal device during expansion thereof, without substantially separating therefrom.

39. A method as in claim 36, wherein a physiological fluid dissolves the therapeutic agent.

40. A method as in claim 39, wherein the physiological fluid comprises blood or cytoplasm.

41. A method as in claim 36, wherein the step of depositing results in swelling of the polymer anchor coating thereby enhancing diffusion of the therapeutic agent into the polymer anchor coating.

42. A method as in claim 36, wherein the metallic substrate comprises a material selected from the group consisting of stainless steel, nickel-titanium alloys and cobalt-chromium alloys.

43. A method as in claim 36, wherein the substance is either in gaseous form under ambient conditions or the substance can be volatilized.

44. A method as in claim 43, wherein the substance comprises a material selected from the group consisting of allyl substituted compounds, acrylic acids, methacrylic acids, acrylates, methacrylates, ethylene glycol, organosilicones, thiophenes, vinyl benzene, vinyl pyrrolidinone, and methane.

45. A method as in claim 36, wherein the polymer anchor coating is continuous over substantially all of a surface of the metallic substrate.

46. A method as in claim 36, wherein the step of exposing the metallic substrate comprises exposing the metallic substrate to a inert diluent noble gas in the presence of the substance to be polymerized.

47. A method as in claim 36, further comprising masking a portion of the substrate so as to selectively apply the polymer anchor coating to the substrate.

48. A method as in claim 36, further comprising controlling the degree of polymerization of the substance.

49. A method as in claim 48, wherein controlling comprises a step selected from the group consisting of limiting power level, limiting exposure time and applying power in a pulsewise manner.

50. A method as in claim 36, further comprising controlling the degree of cross-linking of the substance.

51. A method as in claim 50, wherein controlling comprises a step selected from the group consisting of limiting power level, limiting exposure time and applying power in a pulsewise manner.

52. A method as in claim 36, further comprising cleaning of a surface of the substrate.

53. A method as in claim 36, wherein the therapeutic agent comprises at least one of antibiotics, thrombolytics, anti-platelet agents, anti-inflammatories, cytotoxic agents, anti-proliferative agents, vasodilators, gene therapy agents, radioactive agents, immunosuppressants, chemotherapeutics, endothelial cell attractors, endothelial cell promoters, stem cells, hormones, smooth muscle relaxants, mTOR inhibitors and combinations thereof.

54. A method as in claim 36, wherein the step of depositing comprises one of dipping, spraying, brush coating, syringe deposition, chemical vapor deposition or plasma deposition of the solid layer of the therapeutic agent over the polymer anchor coating.

55. A method as in claim 36, wherein the step of depositing comprises rotating a mandrel with the intraluminal device disposed thereon.

56. A method as in claim 36, wherein the polymeric matrix is a different polymer than the polymer anchor coating.

57. A method as in claim 36, wherein the polymeric matrix biodegrades from the polymer anchor coating over a period not exceeding twenty-four months.

58. A method as in claim 36, wherein the polymeric matrix comprises a first polymer layer disposed over the therapeutic agent.

59. A method as in claim 58, wherein the first layer is adapted to control release rate of the therapeutic agent from the polymeric matrix.

60. A method as in claim 58, wherein the polymeric matrix further comprises a second therapeutic agent disposed over the first polymer layer.

61. A method as in claim 60, wherein the polymeric matrix further comprises a second polymer layer disposed over the second therapeutic agent.

62. A method as in claim 36, wherein the polymeric matrix diffuses into the polymer anchor coating.

63. A method as in claim 36, wherein the polymeric matrix bonds to the polymer anchor coating.

64. A method as in claim 36, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the physiological fluid into the polymeric matrix thereby dissolving the therapeutic agent.

65. A method as in claim 64, wherein the physiological fluid comprises blood or cytoplasm.

66. A method as in claim 36, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the physiological fluid into the polymeric matrix, thereby promoting bioerosion of the matrix.

67. A method as in claim 66, wherein the physiological fluid comprises blood or cytoplasm.

68. A method as in claim 36, wherein the polymer matrix comprises a material selected from the group consisting of polyhydroxyalkanoates, polyalphahydroxy acids, polysaccharides, proteins, hydrogels, lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohols, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride, acrylates, cyanoacrylates, methacrylates and poly(glycerol-sebacate).

69. A method as in claim 36, further comprising varying porosity of the polymer anchor coating in order to control blending of the polymer matrix with the polymer anchor coating thereby controlling release rate of the therapeutic agent from the polymer matrix.

91. A method as in claim 60, wherein the polymeric matrix further comprises a second polymer layer disposed over the second therapeutic agent.

70. A stent for placement in a body lumen, the stent comprising:

a plurality of struts coupled together forming a substantially tubular structure, the plurality of struts having a polymer anchor coating of about 500 Å

in thickness or less disposed thereon and a layer containing a therapeutic agent positioned over the polymer anchor coating, wherein the polymer anchor coating is formed from a gaseous plasma form of a substance that polymerizes on the struts while in the plasma form, and

wherein substantially all of the therapeutic agent is released into a physiological environment gradually over a period ranging from about one hour up to about six months.

71. A stent as in claim 70, wherein the tubular structure is self-expanding.

72. A stent as in claim 70, wherein the tubular structure is balloon expandable.

73. A stent as in claim 70, wherein the polymer anchor coating is adapted to withstand significant cracking during expansion of the stent.

74. A stent as in claim 70, wherein the polymer anchor coating remains coupled to the intraluminal device during expansion thereof, without substantially separating therefrom.

75. A stent as in claim 70, wherein a physiological fluid dissolves the therapeutic agent.

76. A stent as in claim 75, wherein the physiological fluid comprises blood or cytoplasm.

77. A stent as in claim 70, wherein the polymer anchor coating swells upon contact with the therapeutic agent thereby enhancing diffusion of the therapeutic agent into the polymer anchor coating.

78. A stent as in claim 70, wherein the struts are metal.

79. A stent as in claim 78, wherein the plurality of struts comprise a material selected from the group consisting of stainless steel, nickel-titanium alloys and cobalt-chromium alloys.

80. A stent as in claim 70, wherein the struts are a polymer.

81. A stent as in claim 70, wherein the struts are at least partially bioerodible.

82. A stent as in claim 70, wherein the substance is either in gaseous form under ambient conditions or the substance can be volatilized.

83. A stent as in claim 82, wherein the substance comprises a material selected from the group consisting of allyl substituted compounds, acrylic acids, methacrylic acids, acrylates, methacrylates, ethylene glycol, organosilicones, thiophenes, vinyl benzene, vinyl pyrrolidinone, and methane.

84. A stent as in claim 70, wherein the therapeutic agent inhibits restenosis.

85. A stent as in claim 70, wherein the therapeutic agent comprises at least one of antibiotics, thrombolytics, anti-platelet agents, anti-inflammatories, cytotoxic agents, anti-proliferative agents, vasodilators, gene therapy agents, radioactive agents, immunosuppressants, chemotherapeutics, endothelial cell attractors, endothelial cell promoters, stem cells, hormones, smooth muscle relaxants, mTOR inhibitors and combinations thereof.

86. A stent as in claim 70, wherein the polymer anchor coating is continuous over substantially all of a surface of at least one of the struts.

87. A stent as in claim 70, wherein the therapeutic agent is dispersed in a polymeric matrix positioned over the polymer anchor coating.

88. A stent as in claim 70, wherein the polymeric matrix comprises a first polymer layer disposed over the therapeutic agent.

89. A method as in claim 88, wherein the first layer is adapted to control release rate of the therapeutic agent from the polymeric matrix.

90. A method as in claim 88, wherein the polymeric matrix further comprises a second therapeutic agent disposed over the first polymer layer.

92. A stent as in claim 87, wherein the polymeric matrix is a different polymer than the polymer anchor coating.

93. A stent as in claim 87, wherein the polymeric matrix biodegrades from the polymer anchor coating over a period not exceeding twenty-four months.

94. A stent as in claim 87, wherein the polymeric matrix diffuses into the polymer anchor coating.

95. A stent as in claim 87, wherein the polymeric matrix bonds to the polymer anchor coating.

96. A stent as in claim 87, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the fluid into the polymeric matrix thereby dissolving the therapeutic agent.

97. A stent as in claim 96, wherein the physiological fluid comprises blood or cytoplasm.

98. A stent as in claim 87, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the fluid into the polymeric matrix thereby promoting bioerosion of the polymer matrix.

99. A stent as in claim 98, wherein the physiological fluid comprises blood or cytoplasm.

100. A stent as in claim 87, wherein the polymer anchor coating swells upon contact with the polymeric matrix thereby enhancing diffusion of the polymeric matrix into the polymer anchor coating.

101. A stent as in claim 87, wherein the polymer matrix comprises a material selected from the group consisting of polyhydroxyalkanoates, polyalphahydroxy acids, polysaccharides, proteins, hydrogels, lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohols, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride, acrylates, cyanoacrylates, methacrylates and poly(glycerol-sebacate).

102. A method for delivering a therapeutic agent to a target treatment site, the method comprising:

introducing a delivery catheter having a stent disposed thereon to the target treatment site; and

deploying the stent into the target treatment site,

wherein the stent comprises a plurality of struts having a polymer anchor coating of about 500 Å

in thickness or less disposed thereon and a layer containing the therapeutic agent positioned over the polymer anchor coating, wherein the polymer anchor coating is formed from a gaseous plasma form of a substance that polymerizes on the struts while in the plasma form, and

wherein substantially all of the therapeutic agent is released into the target treatment site gradually over a period ranging from about one hour up to about 6 months.

103. A method as in claim 102, wherein the therapeutic agent inhibits restenosis in a blood vessel following release of the therapeutic agent.

104. A method as in claim 102, wherein deploying the stent comprises deploying the stent into an artery.

105. A method as in claim 102, wherein the artery is a coronary artery or a peripheral artery.

106. A method as in claim 102, wherein deploying the stent comprises radially expanding the stent.

107. A method as in claim 106, wherein the stent is self-expanding.

108. A method as in claim 106, wherein deploying the stent comprises expanding a balloon.

109. A method as in claim 102, wherein deploying comprises radially expanding the stent without significant cracking of the polymer anchor coating.

110. A method as in claim 102, wherein deploying comprises radially expanding the stent without substantially separating the polymer anchor coating from the stent.

111. A method as in claim 102, wherein the polymer anchor coating swells upon contact with the therapeutic agent thereby enhancing diffusion of the therapeutic agent into the polymer anchor coating.

112. A method as in claim 102, wherein the substance is either in gaseous form under ambient conditions or the substance can be volatilized.

113. A method as in claim 112, wherein the substance comprises a material selected from the group consisting of allyl substituted compounds, acrylic acids, methacrylic acids, acrylates, methacrylates, ethylene glycol, organosilicones, thiophenes, vinyl benzene, vinyl pyrrolidinone, and methane.

114. A method as in claim 102, wherein the polymer anchor coating is continuous over substantially all of a surface of the struts.

115. A method as in claim 102, wherein the therapeutic agent comprises at least one of antibiotics, thrombolytics, anti-platelet agents, anti-inflammatories, cytotoxic agents, anti-proliferative agents, vasodilators, gene therapy agents, radioactive agents, immunosuppressants, chemotherapeutics, endothelial cell attractors, endothelial cell promoters, stem cells, hormones, smooth muscle relaxants, mTOR inhibitors and combinations thereof.

116. A method as in claim 102, wherein the therapeutic agent is dispersed in a polymeric matrix positioned over the polymer anchor coating.

117. A stent as in claim 116, wherein the polymeric matrix comprises a first polymer layer disposed over the therapeutic agent.

118. A method as in claim 117, wherein the first layer is adapted to control release rate of the therapeutic agent from the polymeric matrix.

119. A method as in claim 117, wherein the polymeric matrix further comprises a second therapeutic agent disposed over the first polymer layer.

120. A method as in claim 119, wherein the polymeric matrix further comprises a second polymer layer disposed over the second therapeutic agent.

121. A method as in claim 116, wherein the polymeric matrix is a different polymer than the polymer anchor coating.

122. A method as in claim 116, wherein the polymeric matrix biodegrades from the polymer anchor coating over a period not exceeding twenty-four months.

123. A method as in claim 116, wherein the polymeric matrix diffuses into the polymer anchor coating.

124. A method as in claim 116, wherein the polymeric matrix bonds to the polymer anchor coating.

125. A method as in claim 116, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the fluid into the polymeric matrix thereby dissolving the therapeutic agent.

126. A method as in claim 125, wherein the physiological fluid comprises blood or cytoplasm.

127. A method as in claim 116, wherein the polymeric matrix is sufficiently porous or absorptive of a physiological fluid to admit the fluid into the polymeric matrix thereby promoting bioerosion of the polymer matrix.

128. A method as in claim 127, wherein the physiological fluid comprises blood or cytoplasm.

129. A method as in claim 116, wherein the polymer anchor coating swells upon contact with the polymeric matrix thereby enhancing diffusion of the polymeric matrix into the polymer anchor coating.

130. A method as in claim 116, wherein the polymer matrix comprises a material selected from the group consisting of polyhydroxyalkanoates, polyalphahydroxy acids, polysaccharides, proteins, hydrogels, lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohols, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride, acrylates, cyanoacrylates, methacrylates and poly(glycerol-sebacate).