Implant with cavities containing therapeutic agents

• US 6,709,379 B1
• Filed: 05/02/2001
• Issued: 03/23/2004
• Est. Priority Date: 11/02/1998
• Status: Expired due to Fees

• Current Assignee: AlCove Surfaces GmbH
• Original Assignee: AlCove Surfaces GmbH
• Inventors: Brandau, Wolfgang, Schmid, Güenter, Sawitowski, Thomas, Fischer, Alfons
• Primary Examiner(s): Bennett, Henry
• Assistant Examiner(s): WIEKER, AMANDA FLYNN
• Application Number:
  US09/830,895
• Time in Patent Office: 1,056 Days
• Field of Search: 600/2-3, 600/7-8, 604/891.1, 604/892.1, 604/890.1, 623/1.39, 623/1-2-, 623/1-5-, 623/1.49
• US Class Current: 600/3
• CPC Class Codes: A61F 2/82 Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95; for closing wounds, or holding wounds closed A61B17/04 - A61B17/115; dilators A61M29/00
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61N 5/1002 Intraluminal radiation therapy
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention relates to an implant and a method for the production of an implant. The implant has a covering layer that is preferably made of aluminium oxide and provided with uniform cavities and separate openings on the surface side of the covering layer in order to receive a therapeutic agent which can be released according to requirements when the implant is in place.

Claims

1. An implant adapted for contacting body tissue and body fluids of humans or animals comprising:

a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings of substantially uniform shape which are homogenously distributed on the surface of and opening to the surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm.

2. An implant, according to claim 1, wherein the support is provided with an electrolytically applied covering layer.

3. An implant, according to claim 1, wherein the support is provided with an oxidized covering layer.

4. An implant, according to claim 1, wherein the support is provided with a plasma deposition applied covering layer.

5. An implant, according to claim 1, wherein said covering layer comprises an oxidized surface of said support.

6. An implant, according to claim 1, wherein said covering layer is formed at least on outside surface portions of the support with essentially uniform thickness.

7. An implant, according to claim 1, wherein said cavities are formed longitudinally.

8. An implant, according to claim 1, wherein said cavities are formed tube-like and are each closed on at least one end.

9. An implant, according to claim 1, wherein said cavities extend essentially perpendicularly to at least one of the surface of said covering layer and the surface of said support.

10. An implant, according to claim 1, wherein said cavities each comprise sections with different dimensioned cross-sections.

11. An implant, according to claim 1, wherein said openings of said cavities are distributedly arranged over at least a portion of the surface of said covering layer with a surface density of 10⁸ to 10¹¹/cm² over said surface.

12. An implant, according to claim 1, wherein the sum of the cross-sectional areas of the openings is at most 50% of the surface.

13. An implant, according to claim 1, wherein said openings comprise essentially the same cross-sectional opening area.

14. An implant, according to claim 1, wherein said openings have a maximum diameter of up to 50 nm.

15. An implant, according to claim 1, wherein said implant is formed as a stent.

16. An implant, according to claim 1, wherein said therapeutic agent is bound in said cavities and releasable therefrom when activated by laser or ultrasound.

17. An implant, according to claim 1, wherein said therapeutic agent is bound in said cavities and releasable therefrom by body-specific substances, body fluids, enzymes or activation substances.

18. An implant, according to claim 1, including at least one therapeutic agent in said cavities.

19. An implant, according to claim 18, wherein said therapeutic agent is chemically bound in said cavities via complexing agents.

20. An implant, according to claim 18, wherein said therapeutic agent is chemically bound in said cavities.

21. An implant, according to claim 18, wherein said therapeutic agent is bound in said cavities and releasable therefrom when a predetermined temperature is exceeded.

22. An implant, according to claim 18, comprising at least two therapeutic agents absorbed in said cavities such that said agents are releasable in succession.

23. An implant, according to claim 18, comprising at least two therapeutic agents absorbed in said cavities such that said agents are releasable at different rates.

24. An implant, according to claim 18, wherein said at least one therapeutic agent comprises radioactive material containing a predetermined amount of at least one radionuclide fixed in said cavities.

25. An implant, according to claim 24, wherein said at radioactive material is chemically bound to a wall of said cavities.

26. An implant, according to claim 24 wherein said radioactive material is selected from the group consisting of radioactive rhenium and technetium.

27. An implant according to claim 1, wherein said covering layer and its openings are at least temporarily covered by a cover layer.

28. An implant, according to claim 27, wherein said cover layer is gold.

29. An implant, according to claim 1, wherein the thickness of said covering layer is less than 1.5 μ

m.

30. An implant, according to claim 1, wherein said covering layer forms a barrier layer which is impermeable to body fluids.

31. An implant, according to claim 1, wherein said covering layer covers substantially the whole surface of the support.

32. An implant, according to claim 1, wherein said cavities are formed exclusively in the covering layer.

33. An implant, according to claim 1, wherein said covering layer comprises cavities with at least one of different cross-sections, volumes and opening areas at the surface of said covering layer.

34. An implant, according to claim 1, wherein said cavities each comprise a section with branched cross-sections.

35. An implant, according to claim 1, wherein said openings have a maximum diameter of 25 nm or less.

36. An implant, according to claim 1, wherein said openings have a maximum diameter of 5 nm or greater.

37. An implant, according to claim 1, wherein said cavities and/or openings have an opening area at the surface of the covering layer which is small as compared with the diameters of the components normally found in blood.

38. A method for making an implant adapted for contacting body tissue and body fluids of humans or animals comprising a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings of substantially uniform shape which are homogenously distributed on the surface of and opening to the surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm, said method comprising the steps of:

subjecting said implant to low pressure in order to evacuate the cavities;

supplying at least one of a binding agent for the therapeutic agent and the therapeutic agent to said cavities; and

returning the pressure to normal.

39. A method, as claimed in claim 38, wherein said supplying is accomplished by dipping said implant into said at least one of said binding agent and said therapeutic agent, respectively.

40. A method, as claimed in claim 38, wherein at least one of said binding agent and said therapeutic agent are incorporated into said cavities by means of ultrasound.

41. A method for making an implant adapted for contacting body tissue and body fluids of humans or animals comprising a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of an electrolytically oxidized metal oxide selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm, said method comprising the steps of:

providing said cavities with at least one of complexing agents and reaction partners for chemically binding the therapeutic agent therein and,

thereafter, introducing said therapeutic agent into said cavities.

42. A method, as claimed in claim 41, wherein said therapeutic agent is incorporated in said cavities by subjecting said implant to low pressure.

43. A method of treating humans or animals with a therapeutic agent comprising:

contacting body tissue or body fluids of said treated human or animal with an implant containing said therapeutic agent, said implant comprising a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings of substantially uniform shape which are homogenously distributed on the surface of and opening to the surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, at least one therapeutic agent in said cavities, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm.

44. A method for making an implant adapted for contacting body tissue and body fluids of humans or animals comprising a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of an electrolytically oxidized metal oxide selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm, said method comprising the step of:

incorporating at least one of a binding agent for a therapeutic agent and a therapeutic agent into said cavities by means of ultrasound.

45. An implant adapted for contacting body tissue and body fluids of humans or animals comprising:

a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed similarly-shaped by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm, including at least one therapeutic agent in said cavities,

wherein said at least one therapeutic agent comprises radioactive material containing a predetermined amount of at least one radionuclide fixed in said cavities, and

wherein said radioactive material is chemically bound in said cavities via sulphur groups.

46. An implant adapted for contacting body tissue and body fluids of humans or animals comprising:

a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed similarly-shaped by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm; and

at least one therapeutic agent in said cavities,

wherein said therapeutic agent is bound in said cavities and releasable therefrom when a predetermined temperature is exceeded.

47. A method for making an implant adapted for contacting body tissue and body fluids of humans or animals comprising a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed similarly-shaped by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm, said method comprising the steps of:

subjecting said implant to low pressure in order to evacuate the cavities;

supplying at least one of a binding agent for the therapeutic agent and the therapeutic agent to said cavities; and

returning the pressure to normal,

wherein at least one of said binding agent and said therapeutic agent are incorporated into said cavities by means of ultrasound.

48. An implant adapted for contacting body tissue and body fluids of humans or animals comprising:

a support including an at least partially formed covering layer, said covering layer having a plurality of cavities with separate openings open to a surface of the covering layer, said cavities being adapted for absorbing at least one therapeutic agent, said covering layer consisting essentially of a metal oxide formed by electrolytic oxidation, said metal oxide being selected from the group consisting of aluminum oxide, magnesium oxide, tantalum oxide, iron oxide and tungsten oxide, said cavities being formed similarly-shaped by the electrolytic oxidation forming said metal oxide, and said openings comprising an opening area wherein the average of either the largest or average diameters of said openings is up to 100 nm,

wherein said therapeutic agent is bound in said cavities and releasable therefrom when activated by laser or ultrasound.