Radiopaque polymeric stents

• US 20060034769A1
• Filed: 09/27/2004
• Published: 02/16/2006
• Est. Priority Date: 08/13/2004
• Status: Abandoned Application

• Current Assignee: Rutgers University
• Original Assignee: Rutgers University
• Inventors: Bolikal, Durgadas, Zeltinger, Joan, Kohn, Joachim B., Schmid, Eric, Brandom, Donald K., Pesnell, Aaron D.
• Application Number:
  US10/952,202
• Publication Number:
  US 20060034769A1
• Time in Patent Office: Days
• US Class Current: 424/9.450
• 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 2250/0098 radio-opaque, e.g. radio-opaque markers
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/18 Materials at least partially X-ray or laser opaque
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

Abstract

Preferred embodiments of the present invention relate to polymeric medical devices, such as stents. More particularly, the polymeric compositions disclosed herein comprise halogen-containing, tyrosine-derived diphenols, optionally in conjunction with other groups, such as dicarboxylic acids and/or poly(alkylene oxide), such that the medical devices made from these polymeric compositions are bioresorbable and inherently radiopaque, and exhibit physicomechanical properties consistent with the intended uses of such devices.

Claims

1. A radiopaque, bioresorbable stent, comprising a bioresorbable polymer comprising sufficient halogen atoms to render the stent inherently radiopaque.

2. The stent of claim 1, wherein said stent further comprises a configuration selected from the group consisting of a sheet stent, a braided stent, a self-expanding stent, a wire stent, a deformable stent, and a slide-and-lock stent.

3. The stent of claim 1, wherein said stent is balloon expandable and comprises at least two substantially non-deforming elements arranged to form a tubular member, the non-deforming elements being slidably or rotationally interconnected for allowing the tabular member to expand from a collapsed diameter to an expanded diameter.

37. The stent of claim 1 or 4, further comprising an effective amount of a therapeutic agent.

38. The stent of claim 37, wherein said amount is sufficient to inhibit restenosis, thrombosis, plaque formation, plaque rupture, and inflammation, and/or promote healing.

39. The stent of claim 1 or 4, wherein said polymer forms a coating on at least a portion of said stent.

40. The stent of claim 39, wherein said polymer coating is adapted to promote a selected biological response.

56. A system for treating a site within a body lumen, comprising a catheter having a deployment means, and the stent of claim 1 or 4, wherein said catheter is adapted to deliver the stent to said site and said deployment means is adapted to deploy the stent.

57. The system of claim 56, wherein said catheter is selected from the group consisting of over-the-wire catheters, coaxial rapid-exchange catheters, and multi-exchange delivery catheters.

122. A method for re-treatment of a body lumen, comprising the steps of:

deploying a first device comprising the radiopaque, bioresorbable stent of claim 1 or 4 along a region within said body lumen, wherein said first device resides therein for a first treatment period until said stent is bioresorbed; and

deploying a second device subsequent to said first treatment period along said region, such that said body lumen retreated.

123. The stent of claim 1, wherein said polymer is not naturally occurring.

124. The stent of claim 1, wherein said polymer further comprises an amino acid.

4. A radiopaque, bioresorbable stent, comprising a polymer comprising one or more units described by Formula I:

wherein each X is independently I or Br, Y1 and Y2 for each diphenol unit are independently between 0 and 4, inclusive, and Y1+Y2 for each diphenol unit is between 1 and 8, inclusive.

wherein each R and R₂ are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N and R₂ further comprises a pendant free carboxylic acid group;

wherein A is either;

wherein R₃ is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkylaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;

wherein P is a poly(C₁-C₄ alkylene glycol) unit;

f is from 0 to less than 1;

g is from 0 to 1, inclusive; and

f+g ranges from 0 to 1, inclusive.

5. The stent of claim 4, wherein iodine and bromine are both present as ring substituents.

6. The stent of claim 4, wherein all X groups are ortho-directed.

7. The stent of claim 4, wherein Y1 and Y2 are independently 2 or less, and Y1+Y2=1, 2, 3 or 4.

8. The stent of claim 4, wherein Y1+Y2=2 or 3.

9. The stent of claim 4, wherein all X groups are iodine.

10. The stent of claim 4, wherein the weight fraction of the poly(C₁-C₄ alkylene glycol) unit is less than about 75 wt %.

11. The stent of claim 4, wherein the weight fraction of the poly(C₁-C₄ alkylene glycol) unit is less than about 50 wt %.

12. The stent of claim 4, wherein the poly(C₁-C₄ alkylene glycol) is poly(ethylene glycol) with a weight fraction of less than about 40 wt %.

13. The stent of claim 4, wherein the weight fraction of the poly(ethylene glycol) unit if between about 1 and about 25 wt %.

14. The stent of claim 4, wherein P may independently be C₁ up to C₁ or copolymers of C₁-C₄.

15. The stent of claim 4, wherein f may vary between 0 and about 0.5.

16. The stent of claim 4, wherein f is less than about 0.25.

17. The stent of claim 4, wherein f is less than about 0.1.

18. The stent of claim 4, wherein f varies from about 0.001 to about 0.08.

19. The stent of claim 4, wherein f varies between about 0.025 and about 0.035.

20. The stent of claim 4, wherein g varies between 0 and 0.5, inclusive.

21. The stent of claim 4, wherein g is greater than about 0.1 to about 0.35.

22. The stent of claim 4, wherein g is from about 0.2 to about 0.3.

23. The stent of claim 4, wherein g varies between about 0.01 and about 0.25.

24. The stent of claim 4, wherein g is between about 0.05 and about 0.15.

25. The stent of claim 4, wherein g is greater than 0.

26. The stent of claim 4, wherein both R and R₂ comprise a pendant COOR₁ group;

wherein for R, the subgroup R₁ is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N; and

wherein for R₂, the subgroup R₁ is a hydrogen atom.

27. The stent of claim 4, wherein each R and R₂ independently has the structure:

wherein R₇ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁-CHJ₂- and (—

CH₂—

)a;

wherein R₈ is selected from the group consisting of —

CH═

CH—

, —

CHJ₁-CHJ₂- and (—

CH₂—

)n;

wherein a and n are independently between 0 and 8 inclusive; and

J₁ and J₂ are independently Br or I; and

wherein, for R₂, the subgroup Q comprises a free c arboxylic acid group, and, for each R, the subgroup Q is selected from the group consisting of hydrogen and carboxylic acid esters and amides, wherein said esters and amides are selected from the group consisting of esters and amides of alkyl and alkylaryl groups containing up to 18 carbon atoms and esters and amides of biologically active compounds.

28. The stent of claim 4, wherein each R and R₂ independently has the structure:

wherein R₅ is an alkyl group containing up to 18 carbon atoms and from 0 to 5 heteroatoms selected from O and N; and

wherein in is an integer from 1 to 8 inclusive; and

wherein, for R₂, the subgroup R₁ is a hydrogen, and, for each R, the subgroup R₁ is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

29. The stent of claim 4, wherein each R and R₂ independently has the structure:

wherein j and m are independently an integer from 1 to 8, inclusive, and wherein, for R₂, the subgroup R₁ is a hydrogen atom, and, for each R, R₁ is independently an alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N.

30. The stent of claim 29, wherein each R₁ subgroup for R is independently an alkyl group ranging from 1 to about 18 carbon atoms containing at least one oxygen atom.

31. The stent of claim 29, wherein each R₁ subgroup for R is independently either ethyl or butyl.

32. The stent of claim 4, wherein A is a —

C(═

O)—

group.

33. The stent of claim 4, wherein A is:

wherein R₃ is a C₄-C₁₂ alkyl, C₈-C₁₄ aryl, or C₈-C₁₄ alkylaryl.

34. The stent of claim 33, wherein R₃ is selected so that A is a moiety of a dicarboxylic acid that is a naturally occurring metabolite.

35. The stent of claim 33, wherein R₃ is selected from the group consisting of —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH— and

(—

CH₂—

)_z; and

wherein z is an integer from 0 to 8, inclusive.

36. The stent of claim 35, wherein R₃ is (—

CH₂—

)_z, wherein z is an integer from 1 to 8, inclusive.

41. A polymer comprising one or more units described by Formula I:

wherein each X is independently I or Br, Y1 and Y2 for each diphenol unit are independently between 0 and 4, inclusive, and Y1+Y2 for each diphenol unit is between 1 and 8, inclusive;

wherein each R and R₂ are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N and R₂ further comprises a pendant free carboxylic acid group;

wherein A is either;

wherein R₃ is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkylaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;

wherein P is a poly(C₁-C₄ alkylene glycol) unit;

f ranges from 0 to less than 1;

g ranges from 0 to 1, inclusive; and

f+g ranges from 0 to 1, inclusive.

42. The polymer of claim 41, wherein each R and R₂ independently has the structure:

wherein j and m are independently an integer from 1 to 8, inclusive, wherein each R₁ subgroup for R is independently an alkyl group ranging from 1 to about 18 carbon atoms and containing from 0 to 5 heteroatoms selected from O and N, and wherein each R₁ subgroup for R₂ is independently a tert-butyl (tB) group or a hydrogen atom;

43. The polymer of claim 41, wherein the weight fraction of the Poly(C₁-C₄ alkylene glycol) unit is less than about 75 wt %.

44. The polymer of claim 41, wherein each R₁ subgroup for R is ethyl or butyl.

45. The polymer of claim 41, wherein g is greater than 0.

46. The polymer of claim 41, wherein P is a poly(ethylene glycol) unit with a weight fraction of less than about 40 wt %.

47. The polymer of claim 41, wherein A is —

C(═

O)—

.

48. The polymer of claim 41, wherein A is:

49. The polymer of claim 48, wherein R₃ is C₄-C₁₂ alkyl, C₈-C₁₄ aryl, or C₈-C₁₄ alkylaryl.

50. The polymer of claim 48, wherein R₃ is selected from the group consisting of —

CH₂—

C(═

O)—

, —

CH₂—

CH₂—

C(═

O)—

, —

CH═

CH— and

(—

CH₂—

)z, wherein z is an integer from 0 to 8, inclusive.

51. The polymer of claim 41, wherein f is from about 0.001 to about 0.08.

52. The polymer of claim 41, wherein f is between about 0.025 and about 0.035.

53. The polymer of claim 41, wherein g is about 0.05 to about 0.15.

54. The polymer of claim 41, wherein all X groups are ortho-directed, and Y1+Y2=1, 2, 3 or 4.

55. The polymer of claim 41, wherein every X group is iodine.

58. A method for selective removal of a tert-butyl ester group from a hydrolytically unstable polymer to form a new polymer composition having a free carboxylic acid group in place of said tert-butyl ester group, said method comprising dissolving said hydrolytically unstable copolymer in a solvent comprising an amount of an acid having a pKa from about 0 to about 4 that is effective to selectively remove by acidolysis said tert-butyl ester group to form said new polymer composition having a free carboxylic acid group.

59. The method of claim 58, wherein said hydrolytically unstable polymer is soluble in said solvent.

60. The method of claim 58, wherein said solvent consists essentially of said acid.

61. The method of claim 58, wherein said solvent is selected from the group consisting of chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, and mixtures thereof.

62. The method of claim 58, wherein said acid is selected from the group consisting of formic acid, trifluoroacetic acid, chloroacetic acid, and mixtures thereof.

63. The method of claim 58, wherein said acid is formic acid.

64. The method of claim 58, wherein said hydrolytically unstable polymer comprises one or more units described by Formula II:

wherein X for each polymer unit is independently Br or I, Y is between 0 and 4, inclusive, and R₄ is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and further comprising a pendent tert-butyl ester group.

65. The method of claim 64, wherein said hydrolytically unstable polymer is copolymerized with up to about 75 wt % of a poly(C₁-C₄ alkylene glycol).

66. The method of claim 65, wherein said poly(C₁-C₄ alkylene glycol) weight faction is less than about 40 wt %.

67. The method of claim 64, wherein all X groups are ortho-directed, and Y is 1 or 2.

68. The method of claim 64, wherein every X is iodine.

69. The method of claim 64, wherein R₄ is an alkyl group.

70. The method of claim 69, wherein said R₄ has the structure:

wherein R₂ is independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O or N, and further comprises a pendant t-butyl ester group; and

R_5a and R₆ are each independently selected from hydrogen and straight and branched alkyl groups having up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N.

71. The method of claim 70, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and each R₁ is a tert-butyl ester group.

72. The method of claim 71, wherein said polymer is copolymerized with up to about 75 wt % of a poly(C₁-C₄ alkylene glycol) having a molecular weight of 10,000 or less.

73. The method of claim 72, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 25 wt %.

74. The method of claim 64, wherein R₄ of said polymer unit is an aryl or alkylaryl group.

75. The method of claim 64, wherein said units described by Formula II comprise a diphenol unit.

76. The method of claim 75, wherein R₄ is an alkylaryl group and said diphenol unit is described by Formula III:

wherein X for each polymer unit is independently Br or I, Y1 and Y2 are independently between 0 and 4 inclusive, Y1+Y2 is between 0 and 8, inclusive, and R₂ for each unit is independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and R₂ further comprises a pendant t-butyl ester group.

77. The method of claim 76, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and R₁ is a tert-butyl ester group.

78. The method of claim 76, wherein said polymer is copolymerized with up to about 75 wt % of a poly(C₁-C₄ alkylene glycol).

79. The method of claim 78, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 40 wt %.

80. The method of claim 76, wherein all X groups are ortho-directed, and Y1+Y2=1, 2, 3 or 4.

81. The method of claim 76, wherein every X is iodine.

82. The method of claim 58, wherein said hydrolytically unstable polymer comprises one or more units defined by Formula I:

wherein each X is independently I or Br, Y1 and Y2 for each diphenol unit are independently between 0 and 4, inclusive, and Y1+Y2 for each diphenol unit is between 0 and 8, inclusive.

wherein R and R₂ for each unit are independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and R₂ further comprises a pendant-t-butyl ester group;

wherein A is either;

wherein R₃ is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl, or alkylaryl group containing up to about 18 carbon atoms and 0 to 8 heteroatoms selected from O and N;

wherein P is a poly(C₁-C₄ alkylene glycol) unit;

f ranges from 0 to less than 1;

g ranges from 0 to 1, inclusive; and

f+g ranges from 0 to 1, inclusive.

83. The method of claim 82, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and R, the subgroup R is independently a straight-chain or branched alkyl group ranging from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N; and

for R₂, the subgroup R₁ is a tert-butyl ester (tB) group.

84. The method of claim 82, wherein all X groups are ortho-directed, and Y1+Y2=1, 2, 3 or 4.

85. The method of claim 62, wherein every X is iodine.

86. A polymer comprising one or more units described by Formula II:

wherein X for each polymer unit is independently Br or I, Y is between 0 and 4, inclusive, and R₄ is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and further comprising a pendent tert-butyl ester group.

87. The polymer of claim 86, wherein said polymer is copolymerized with up to about 75 wt % of a poly(C₁-C₄ alkylene glycol).

88. The polymer of claim 87, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 40 wt %.

89. The polymer of claim 86, wherein all X groups are ortho-directed, and Y is 1 or 2.

90. The polymer of claim 86, wherein every X is iodine.

91. The polymer of claim 86, wherein R₄ is an alkyl group.

92. The polymer of claim 86, wherein said R₄ has the structure:

wherein R₂ is independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O or N, and further comprises a pendant t-butyl ester group; and

R_5a and R₆ are each independently selected from hydrogen and straight and branched alkyl groups having up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N.

93. The polymer of claim 86, wherein R₂ comprises:

wherein j and m are in independently an integer from 1 to 8, inclusive, and wherein each R₁ is a tert-butyl ester group.

94. The polymer of claim 86, wherein said polymer is copolymerized with up to about 50 wt % of a poly(C₁-C₄ alkylene glycol) having a molecular weight of 10,000 or less.

95. The polymer of claim 86, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 25 wt %.

96. The polymer of claim 86, wherein of said polymer unit is an aryl or alkylaryl group.

97. The polymer of claim 86, wherein said units described by Formula II comprise a diphenol unit.

98. The polymer of claim 97, wherein R₄ is an alkylaryl group and said diphenol unit is described by Formula III:

wherein X for each polymer unit is independently Br or I, Y1 and Y2 are independently between 0 and 4 inclusive, Y1+Y2 is between 0 and 8, inclusive, and R₂ for each unit is in independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and R₂ further comprises a pendant t-butyl ester group.

99. The polymer of claim 98, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and R₁ is a tert-butyl ester group.

100. The polymer of claim 98, wherein said polymer is copolymerized with up to about 50 wt % of a poly(C₁-C₄ alkylene glycol).

101. The polymer of claim 100, wherein said poly(C₁-C₄ alkylene glycol) weight fraction is less than about 40 wt %.

102. The polymer of claim 98, wherein all X groups are ortho-directed, and Y1+Y2=1, 2, 3 or 4.

103. A compound having a structure described by Formula IIa:

wherein X is Br or I, Y is between 0 and 4, inclusive, and R₄ is an alkyl, aryl or alkylaryl group with up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and further comprises a pendent tert-butyl ester group.

104. The compound of claim 103, wherein all X groups are ortho-directed, and Y=1, 2, 3 or 4.

105. The compound of claim 103, wherein every X group is iodine.

106. The compound of claim 103, wherein R₄ is an alkyl group.

107. The compound of claim 106, wherein said alkyl group has the structure:

wherein R₂ is independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O or N, and further comprises a pendant t-butyl ester group; and

R_5a and R₆ are each independently selected from hydrogen and straight and branched alkyl groups having up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N.

108. The compound of claim 107, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and wherein each R₁ is a tert-butyl ester group.

109. The compound of claim 108, wherein all X groups are ortho-directed, and Y=1, 2, 3 or 4.

110. The compound of claim 108, wherein every X group is iodine

111. The compound of claim 103, wherein R₄ of said polymer unit is an aryl or alkylaryl group.

112. The compound of claim 111, wherein Formula IIa comprises a diphenol unit.

113. The compound of claim 112, wherein R₄ is an alkylaryl group and said diphenol unit is described by Formula IIa:

wherein each X is independently Br or I, Y1 and Y2 are independently between 0 and 4 inclusive, Y1+Y2 is between 0 and 8, inclusive, and R₂ is independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and R₂ further comprises a pendant t-butyl ester group.

114. The compound of claim 113, wherein R₂ comprises:

wherein j and m are independently an integer from 1 to 8, inclusive, and R₁ is a tert-butyl ester group.

115. The compound of claim 113, wherein all X groups are ortho-directed, and Y1+Y2=1, 2, 3 or 4.

116. The compound of claim 113, wherein every X group is iodine.

117. A compound having the structure:

118. A compound having the structure:

119. A compound having the structure:

120. A compound having the structure:

121. A compound having the structure: