Device for local drug delivery and methods for using the same

• US 5,523,092 A
• Filed: 01/28/1994
• Issued: 06/04/1996
• Est. Priority Date: 04/14/1993
• Status: Expired due to Fees

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Hanson, Stephen R., Scott, Neal A., King, Spencer B. III, Harker, Laurence A.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/188,248
• Time in Patent Office: 858 Days
• Field of Search: 604/96, 604/101, 604/264, 604/280, 604/281, 424/423
• US Class Current: 424/423
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/064 with special features to facilitate anastomotic coupling anastomosis of natural blood vessels A61B17/11
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61M 2025/0063 having means, e.g. stylets, mandrils, rods or wires to reinforce or adjust temporarily the stiffness, column strength or pushability of catheters which are already inserted into the human body
• CPC Class Codes: A61M 25/0021 characterised by the form of the tubing A61M25/0054 takes precedence
• CPC Class Codes: A61M 25/0041 pre-formed, e.g. specially adapted to fit with the anatomy of body channels urethral catheters A61F2/04
• CPC Class Codes: A61M 25/0068 Static characteristics of the catheter tip, e.g. shape, atraumatic tip, curved tip or tip structure
• CPC Class Codes: A61M 25/007 Side holes, e.g. their profiles or arrangements; Provisions to keep side holes unblocked
• CPC Class Codes: A61M 25/0102 Insertion or introduction using an inner stiffening member, e.g. stylet or push-rod
• CPC Class Codes: A61M 37/00 Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04

Abstract

A device for the local delivery of a substance into a natural tissue conduit in the mammalian body. The device has a substance delivery segment which provides a means for locally delivering a substance into the boundary layer of fluid flowing through the conduit without disrupting the fluid flow therethrough. For example, an indwelling catheter is provided for endovascular delivery of a substance locally to a targeted treatment area. Also provided are methods of locally delivering a substance into a natural tissue conduit in the mammalian body utilizing the device of the present invention.

Claims

1. A device for the local delivery of a biologically active substance at a predetermined site in a natural tissue conduit in the mammalian body, the conduit having a luminal surface defining a lumen, comprising:

a) an elongated flexible tube of a preselected length and diameter having an external surface, a proximal end, an opposite distal end, and a lumen extending longitudinally therethrough interconnecting the proximal and distal ends with the proximal end defining an opening therethrough, the tube having a substance delivery segment adjacent the distal end and defining a plurality of substance delivery holes through the external surface which are in fluid communication with the lumen of the tube, the substance delivery segment being moveable among a first rest position wherein it has a first shape, a second position wherein it has a second substantially linear shape, and a third operative position wherein it has a third shape, the third position being intermediate the first and second positions;

b) means for moving the substance delivery segment from its first position to its second position, the substance delivery segment tending to return to the first position when the moving means is no longer applied to the substance delivery segment; and

c) means for introducing the substance into the lumen of the tube for delivery into the natural tissue conduit.

2. The device of claim 1, wherein the substance delivery segment assumes the third position when the moving means is no longer applied thereto, such that the substance delivery segment is capable of exerting a force against the luminal surface of the conduit in the third position sufficient to anchor the substance delivery segment at the predetermined site within the lumen of a natural tissue conduit.

3. The device of claim 1, wherein the first shape comprises a plurality of spiral turns of the substance delivery segment about the longitudinal axis of the device such that the substance delivery segment forms a hollow coil and the substance delivery holes are at a preselected location on the coil.

4. The device of claim 3, wherein the preselected location of the substance delivery holes is that the holes are juxtaposed to the luminal surface of the conduit such that a substance delivered therethrough directly contacts the luminal surface of the tissue conduit.

5. The device of claim 3, wherein the preselected location of the substance delivery holes is that the holes are adjacent to the luminal surface of the conduit such that a substance delivered therethrough is delivered into the natural tissue conduit adjacent the luminal surface thereof.

6. The device of claim 3, wherein the preselected location of the substance delivery holes is that the holes are opposite a portion of the external surface of the substance delivery segment which contacts the luminal surface of the conduit such that a substance delivered therethrough is delivered into the boundary layer of a fluid flowing through the lumen of the natural tissue conduit.

7. The device of claim 1, wherein the distal end of the tube further defines an opening therethrough which is in fluid communication with the lumen of the tube and the opening defined by the proximal end thereof.

8. The device of claim 7, wherein the substance delivery segment is substantially linear in the second position and the moving means comprises a guidewire having a distal tip which is removably insertable into the proximal opening of the lumen of the tube and through the opening of the distal end thereof, the guidewire being sufficiently stiff to maintain the substance delivery segment in the second position, thereby allowing deployment of the substance delivery segment through the conduit to the predetermined site.

9. The device of claim 1, wherein the proximal opening of the lumen of the tube is moveable between a closed position which forms a fluid tight seal and an open position which allows a guidewire to pass therethrough.

10. The device of claim 7, wherein the distal opening of the lumen of the tube is moveable between a closed position which forms a fluid tight seal and an open position which allows a guidewire to pass therethrough.

11. The device of claim 1, wherein the distal end of the tube forms a fluid tight seal of the lumen of the tube and the device further comprises a guidewire having a distal tip and a proximal anchoring end, the guidewire being mounted in the tube at the distal end thereof for guiding the tube through the lumen of the natural tissue conduit to the predetermined site.

12. The device of claim 11, wherein the substance delivery segment is substantially linear in the second position and the moving means comprises a stylette having a distal tip which is removably insertable into the proximal opening of the lumen of the tube, through the lumen of the tube to the distal end thereof, the stylette being sufficiently stiff to maintain the substance delivery segment in the second position, thereby allowing deployment of the substance delivery segment through the conduit to the predetermined site.

13. The device of claim 1, wherein the substance delivery segment is comprised of a resilient biocompatible material selected from the group consisting of polymer, synthetic rubber, natural rubber, metal and plastic preformed to into the first shape such that the substance delivery segment normally rests in the first position.

14. The device of claim 13, wherein the material is a non-biodegradable polymer selected from the group consisting of polyurethane, polyethylene, polyethylene terephthalate, polytetrafluoroethylene, ethylene vinyl acetate, polyimid, and nylon.

15. The device of claim 13, wherein the material is a biodegradable polymer selected from the group consisting of polylactic acid and polyglycolic acid.

16. The device claim 13, wherein the material is a metal selected from the group consisting of stainless steel, and tantalum, platinum and nitinol.

17. The device claim 16, wherein the metal is nitinol and wherein the moving means comprises exposing the nitinol to a fluid having a temperature of between about 40°

-65°

C.

18. The device claim 17, wherein the metal is nitinol and wherein the moving means comprises exposing the nitinol to a fluid having a temperature of about 55°

C.

19. The device claim 17, wherein the fluid is selected from the group consisting of ringer'"'"'s solution, lactated ringer'"'"'s solution, 5% dextrose solution, 10% dextrose solution, normal saline solution, 1/2 normal saline solution, 5% dextrose and 1/2 normal saline solution, and sterile water.

20. The device of claim 1, further comprising a semi-permeable membrane covering the external surface of the substance delivery segment and the substance delivery holes defined therein such that delivery of a substance through the substance delivery holes to the predetermined site occurs at a preselected rate.

21. The device of claim 20, wherein the semi-permeable membrane is comprised of a biocompatible material selected from the group consisting of a biodegradable polymer and a non-biodegradable polymer.

22. The device of claim 21, wherein the semi-permeable membrane is a non-biodegradable polymer selected from the group consisting of polytetrafluoroethylene, ethylene vinyl acetate, polyethylene, and polyethylene terephthalate.

23. The device of claim 20, wherein the substance is a fluid and the preselected rate is between about 0.01 and 1.0 ml/minute.

24. The device of claim 1, wherein the substance introducing means comprises an infusion port attached to the tube adjacent the proximal end which is in fluid communication with the lumen of the tube such that a substance can be delivered through the port and into the lumen of the natural tissue conduit.

25. The device of claim 1, further comprising at least one opening through the external surface of the tube which is in fluid communication with the lumen of the tube, the opening being located between the substance delivery segment and the proximal end of the tube such that at least a portion of a substance delivered into the lumen of the tube can pass into the natural tissue conduit through said opening.

26. The device of claim 1, wherein the conduit is a blood vessel.

27. The device of claim 1, wherein the substance is a drug.

55. A method for providing local delivery of a biologically active substance to a predetermined site in a natural conduit in the mammalian body, the conduit having a luminal surface defining a lumen, comprising the steps of:

a) placing the device of claim 1 in the lumen of the natural tissue conduit adjacent the predetermined site; and

b) delivering a substance to the predetermined site via the substance delivery device without interrupting the flow of a fluid through the conduit.

56. The method of claim 55, wherein the predetermined site is the boundary layer of fluid flowing through the natural tissue conduit.

57. The method of claim 55, wherein the predetermined site is the boundary layer of fluid flowing through the natural tissue conduit upstream of a target treatment area.

58. The method of claim 55, wherein the natural tissue conduit is a blood vessel.

59. The method of claim 55, wherein the substance is a drug.

60. The method of claim 55, wherein the substance is an anticoagulant.

61. The method of claim 60, wherein the anticoagulant is selected from the group consisting of heparin, hirudin, hirulog, hirugen, activated and non-activated protein C, synthetic antagonists of thrombin, Factor VIIa, Factor Xa and activated and non-activated coagulation factors.

62. The method of claim 55, wherein the substance antagonizes platelet deposition and thrombus formation.

63. The method of claim 62, wherein the substance is selected from the group consisting of:

plasmin, tissue plasminogen activator (tPA), urokinase (UK), single chain prourokinase (scuPA), streptokinase;

prostaglandins, cyclooxygenase inhibitors, phosphodiesterase inhibitors, thromboxane synthetase inhibitors;

antagonists of glycoprotein receptors including (GP) Ib,GP IIb/IIIa, antagonists of collagen receptors, and antagonists of platelet thrombin receptors.

64. The method of claim 55, wherein the substance affects platelet metabolic function.

65. The method of claim 64, wherein the substance is selected from the group consisting of prostaglandins, cyclooxygenase inhibitors, phosphodiesterase inhibitors, thromboxane inhibitors, inhibitors of calcium transport, and cyclic AMP agonists.

66. The method of claim 55, wherein the substance prevents restenosis in a blood vessel.

67. The method of claim 66, wherein the substance is selected from the group consisting of a growth factor, a growth factor inhibitor, growth factor receptor antagonist, transcriptional repressor, translational repressor, antisense DNA, antisense RNA, replication inhibitor, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules comprising a growth factor and a cytotoxin, and bifunctional molecules comprising an antibody and a cytotoxin.

68. The method of claim 55, wherein the substance is a vasodilator.

69. The method of claim 68, wherein the substance is selected from the group consisting of nitroglycerin, nitroprusside, agents which liberate nitric oxide, and agents which inhibit calcium transport.

28. A device for the local delivery of a biologically active substance at a predetermined site in a natural tissue conduit in the mammalian body, the conduit having a luminal surface defining a lumen, comprising:

a) an elongated flexible tube of a preselected length and diameter having an external surface, a proximal end, an opposite distal end, and a first lumen extending longitudinally therethrough interconnecting the proximal and distal ends with the proximal end defining an opening in the first lumen, the tube having a substance delivery segment adjacent the distal end and defining a plurality of substance delivery holes through the external surface, an infusion port located adjacent the proximal end of the tube, and a second lumen within the tube interconnecting the infusion port with the substance delivery holes so that a substance can be delivered through the infusion port, the second lumen, and the substance delivery holes to the predetermined site, the substance delivery segment being moveable among a first rest position wherein it has a first shape, a second position wherein it has a second substantially linear shape, and a third operative position wherein it has a third shape, the third position being intermediate the first and second positions; and

b) means for moving the substance delivery segment from its first position to its second position, the substance delivery segment tending to return to the first position when the moving means is no longer applied to the substance delivery segment.

29. The device of claim 28, wherein the substance delivery segment assumes the third position when the moving means is no longer applied thereto, such that the substance delivery segment is capable of exerting a force against the luminal surface of the conduit in the third position sufficient to anchor the substance delivery segment at the predetermined site within the lumen of a natural tissue conduit.

30. The device of claim 28, wherein the first shape comprises a plurality of spiral turns of the substance delivery segment about the longitudinal axis of the device such that the substance delivery segment forms a hollow coil and the substance delivery holes are at a preselected location on the coil.

31. The device of claim 30, wherein the preselected location of the substance delivery holes is that the holes are juxtaposed to the luminal surface of the conduit such that a substance delivered therethrough directly contacts the luminal surface of the tissue conduit.

32. The device of claim 30, wherein the preselected location of the substance delivery holes is that the holes are adjacent to the luminal surface of the conduit such that a substance delivered therethrough is delivered into the natural tissue conduit adjacent the luminal surface thereof.

33. The device of claim 30, wherein the preselected location of the substance delivery holes is that the holes are opposite a portion of the external surface of the substance delivery segment which contacts the luminal surface of the conduit such that a substance delivered therethrough is delivered into the boundary layer of a fluid flowing through the lumen of the natural tissue conduit.

34. The device of claim 28, wherein the distal end of the tube further defines an opening therethrough which is in fluid communication with the first lumen of the tube and the opening defined by the proximal end thereof.

35. The device of claim 34, wherein the substance delivery segment is substantially linear in the second position and the moving means comprises a guidewire having a distal tip which is removably insertable into the proximal opening of the first lumen of the tube and through the opening of the distal end thereof, the guidewire being sufficiently stiff to maintain the substance delivery segment in the second position, thereby allowing deployment of the substance delivery segment through the conduit to the predetermined site.

36. The device of claim 28, wherein the proximal opening of the first lumen of the tube is moveable between a closed position which forms a fluid tight seal and an open position which allows the guidewire to pass therethrough.

37. The device of claim 34, wherein the distal opening of the first lumen of the tube is moveable between a closed position which forms a fluid tight seal and an open position which allows the guidewire to pass therethrough.

38. The device of claim 28, wherein the distal end of the tube forms a fluid tight seal of the lumen of the tube and the device further comprises a guidewire having a distal tip and a proximal anchoring end, the guidewire being mounted in the tube at the distal end thereof for guiding the tube through the lumen of the natural tissue conduit to the predetermined site.

39. The device of claim 38, wherein the substance delivery segment is substantially linear in the second position and the moving means comprises a stylette having a distal tip which is removably insertable into the proximal opening of the lumen of the tube, through the lumen of the tube to the distal end thereof, the stylette being sufficiently stiff to maintain the substance delivery segment in the second position, thereby allowing deployment of the substance delivery segment through the conduit to the predetermined site.

40. The device of claim 28, wherein the substance delivery segment is comprised of a resilient biocompatible material selected from the group consisting of polymer, synthetic rubber, natural rubber, metal and plastic preformed to into the first shape such that the substance delivery segment normally rests in the first position.

41. The device of claim 40, wherein the material is a non-biodegradable polymer selected from the group consisting of polyurethane, polyethylene, polyethylene terephthalate, polytetrafluoroethylene, ethylene vinyl acetate, polyimide and nylon.

42. The device of claim 40, wherein the material is a biodegradable polymer selected from the group consisting of polylactic acid and polyglycolic acid.

43. The device claim 40, wherein the material is a metal selected from the group consisting of stainless steel, and tantalum, platinum and nitinol.

44. The device claim 43, wherein the metal is nitinol and wherein the moving means comprises exposing the nitinol to a fluid having a temperature of between about 40°

-65°

C.

45. The device claim 44, wherein the metal is nitinol and wherein the moving means comprises exposing the nitinol to a fluid having a temperature of about 55°

C.

46. The device claim 44, wherein the fluid is selected from the group consisting of ringer'"'"'s solution, lactated ringer'"'"'s solution, 5% dextrose solution, 10% dextrose solution, normal saline solution, 1/2 normal saline solution, 5% dextrose and 1/2 normal saline solution, and sterile water.

47. The device of claim 28, further comprising a semi-permeable membrane covering the external surface of the substance delivery segment and the substance delivery holes defined therein such that delivery of a substance through the substance delivery holes to the predetermined site occurs at a preselected rate.

48. The device of claim 47, wherein the semi-permeable membrane is comprised of a biocompatible material selected from the group consisting of a biodegradable polymer and a non-biodegradable polymer.

49. The device of claim 47, wherein the semi-permeable membrane is a non-biodegradable polymer selected from the group consisting of polytetrafluoroethylene, ethylene vinyl acetate, polyethylene, and polyethylene terephthalate.

50. The device of claim 47, wherein the substance is a fluid and the preselected rate is between about 0.01 and 1.0 ml/minute.

51. The device of claim 28, wherein the substance introducing means comprises an infusion port attached to the tube adjacent the proximal end which is in fluid communication with the lumen of the tube such that a substance can be delivered through the port and into the lumen of the natural tissue conduit.

52. The device of claim 28, further comprising at least one opening through the external surface of the tube which is in fluid communication with the lumen of the tube, the opening being located between the substance delivery segment and the proximal end of the tube such that a portion of a substance delivered into the lumen of the tube passes into the natural tissue conduit through said opening.

53. The device of claim 28, wherein the conduit is a blood vessel.

54. The device of claim 28, wherein the substance is a drug.