Device for in vivo delivery of bioactive agents and method of manufacture thereof

• US 20050186241A1
• Filed: 09/09/2004
• Published: 08/25/2005
• Est. Priority Date: 11/17/2000
• Status: Active Grant

• Current Assignee: Vactronix Scientific, LLC
• Original Assignee: Advanced Bio Prosthetic Surfaces, Ltd.
• Inventors: Banas, Christopher E., Bailey, Steven R., Marton, Denes, Boyle, Christopher T.
• Granted Patent: US 9,107,605 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61B 5/01 Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue clinical contact thermometers G01K13/20
• CPC Class Codes: A61B 5/02055 Simultaneously evaluating both cardiovascular condition and temperature
• CPC Class Codes: A61B 5/021 Measuring pressure in heart or blood vessels A61B5/0205 takes precedence
• CPC Class Codes: A61B 5/0215 by means inserted into the body catheters A61M25/00
• CPC Class Codes: A61B 5/026 Measuring blood flow A61B3/1233, A61B3/1241 take precedence
• CPC Class Codes: A61B 5/076 Permanent implantations telemetry using implanted circuitry A61B5/0031; implanted stimulators for therapy A61N1/3605, A61N1/362, A61N1/372
• CPC Class Codes: A61B 5/4839 combined with drug delivery
• CPC Class Codes: A61B 5/6862 Stents
• CPC Class Codes: A61B 5/6876 Blood vessel
• CPC Class Codes: A61F 2/07 Stent-grafts
• 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 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 2002/91533 characterised by the phase between adjacent bands
• CPC Class Codes: A61F 2002/91541 Adjacent bands are arranged out of phase
• CPC Class Codes: A61F 2002/91558 connected peak to peak
• CPC Class Codes: A61F 2210/0076 multilayered, e.g. laminated structures
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0001 Means for transferring electromagnetic energy to implants
• CPC Class Codes: A61F 2250/0067 : Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 2250/0068 : the pharmaceutical product being in a reservoir
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/04 : Metals or alloys
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/022 : Metals or alloys
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

The present invention consists of an implantable structural element for in vivo controlled delivery of bioactive active agents to a situs in a body. The implantable structural element may be configured as an implantable prosthesis, such as an endoluminal stent, cardiac valve, osteal implant or the like, which serves a dual function of being prosthetic and a carrier for a bioactive agent. Control over elution of the bioactive agents occurs through a plurality of cantilever-like cover members which prevent drug elution until an endogenous or exogenous stimulus causes the cover members to open and permit drug elution.

Claims

1. An implantable drug-eluting medical device, comprising a first member having a plurality of wall surfaces defining a z-axis thickness of the first member, at least one internal chamber enclosed entirely within the z-axis thickness of the first member, at least one of a plurality of openings communicating between the internal chamber and at least one of the plurality of wall surfaces and through a portion of the z-axis thickness of the first member, a bioactive agent within the at least one internal chamber, and a plurality of second members disposed upon the at least one of the plurality of wall surfaces, at least one of the plurality of second members associated with the at least one of a plurality of openings, each of the at least one of a plurality of second members having a first position which covers and occludes an associated opening and a second position which uncovers the associated opening, the plurality of second members being capable of transitioning between the first position and the second position upon encountering a defined stimulus.

2. The implantable drug-eluting medical device according to claim 1, wherein the plurality of second members are in the first position in their native state and transition to the second position upon application of a stimulus.

3. The implantable drug-eluting medical device according to claim 1, wherein the stimulus is an exogenous stimulus applied transcutaneously to the medical device.

4. The implantable drug-eluting medical device according to claim 1, wherein the stimulus is selected from the group consisting of endogenous physical, electrical or chemical stimuli.

5. The implantable drug-eluting medical device according to claim 1, wherein the first member is selected from the group of stent, covered stents and vascular grafts.

6. The implantable drug-eluting medical device according to claim 1, wherein the first member further comprises a stent being having a plurality of interconnected individual structural elements, at least some of the plurality of interconnected individual structural elements having the at least one internal chamber, the at least one of a plurality of openings, the at least one bioactive agent therein and at least one of a plurality of covering members operably associated with the at least one of a plurality of openings.

7. The implantable body according to claim 1, wherein the first member and the plurality of second members each further comprise a material selected from the group consisting of titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum and alloys thereof, zirconium-titanium-tantalum alloy, nickel-titanium alloy, nickel-titanium-tantalum alloy, chromium-cobalt alloy, and stainless steel.

8. The implantable body according to claim 1, wherein the bioactive agent further comprises a pharmacologically active agent selected from the group of antibiotic drugs, antiviral drugs, neoplastic agents, steroids, fibronectin, anti-clotting drugs, anti-platelet function drugs, drugs which prevent smooth muscle cell growth on inner surface wall of vessel, heparin, heparin fragments, aspirin, coumadin, tissue plasminogen activator, urokinase, hirudin, streptokinase, antiproliferative agents, antioxidants, antimetabolites, thromboxane inhibitors, non-steroidal and steroidal anti-inflammatory drugs, immunosuppresents, beta and calcium channel blockers, genetic materials including DNA and RNA fragments, complete expression genes, antibodies, lymphokines, growth factors, vascular endothelial growth factor, fibroblast growth factor, prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide, integrins, paclitaxel, taxol, rapamycin, rapamycin derivatives and analogues, sirolimus, rapamune, tacrolimus, dexamethasone, everolimus, ABT-578 and growth factors.

9. An endoluminal stent, comprising a generally tubular member having a central lumen passing longitudinally through the tubular member and open at opposing ends of the tubular member, a luminal surface and an abluminal surface and a wall thickness defined therebetween, at least one internal chamber defined entirely within the wall thickness in at least some portions of the tubular member, a plurality of openings communicating between the at least one internal chamber and at least one of the luminal surface, abluminal surface, at least one bioactive agent disposed in the at least one internal chamber and a plurality of cover members operably associated with the plurality of openings and having a closed position which occludes at least one of the plurality of openings and an open position which permits the at least one bioactive agent to elute from the at least one internal chamber and through the at least one opening.

10. The implantable body according to claim 9, wherein the tubular member and the plurality of cover members further comprise a material selected from the group consisting of titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum and alloys thereof, zirconium-titanium-tantalum alloys, nickel titanium alloy, chromium-cobalt alloy, and stainless steel.

11. The implantable drug-eluting medical device according to claim 10, wherein at least one of the tubular member and the plurality of cover members are fabricated of at least one biocompatible thin metallic film.

12. The implantable body according to claim 9, wherein the at least one bioactive agent further comprises a pharmacologically active agent selected from the group of antibiotic drugs, antiviral drugs, neoplastic agents, steroids, fibronectin, anti-clotting drugs, anti-platelet function drugs, drugs which prevent smooth muscle cell growth on inner surface wall of vessel, heparin, heparin fragments, aspirin, coumadin, tissue plasminogen activator, urokinase, hirudin, streptokinase, antiproliferative agents, antioxidants, antimetabolites, thromboxane inhibitors, non-steroidal and steroidal anti-inflammatory drugs, immunosuppresents, beta and calcium channel blockers, genetic materials including DNA and RNA fragments, complete expression genes, antibodies, lymphokines, growth factors, vascular endothelial growth factor, fibroblast growth factor, prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide, integrins, paclitaxel, taxol, rapamycin, rapamycin derivatives and analogues, sirolimus, rapamune, tacrolimus, dexamethasone, everolimus, ABT-578 and growth factors.

13. An endoluminal stent according to claim 9, wherein the tubular member further comprises a plurality of interconnected structural elements defining walls of the tubular member, a plurality of discontinuous interior chambers associated with at least some of the plurality of structural elements, a plurality of openings communicating between each of the plurality of discontinuous interior cavities and external the stent, at least one bioactive agent disposed within the plurality of discontinuous interior chambers, and at least one of a plurality of cantilever-like cover members associated with the plurality of openings.

14. A method of making a drug-eluting medical device, comprising the steps of:

a) Vacuum depositing a first layer of a biocompatible material onto a substrate;

b) Vacuum deposing a sacrificial layer of material onto the first layer of a biocompatible material;

c) Removing portions of the sacrificial layer to form internal chamber defining regions of the sacrificial layer;

d) Vacuum depositing a second layer of biocompatible material onto the internal chamber defining regions of the sacrificial layer and the first layer of biocompatible material;

e) Forming at least one of a plurality of openings passing through the second layer of biocompatible and communicating with the internal chamber defining regions of the sacrificial layer;

f) Removing the internal chamber defining regions of the sacrificial layer thereby forming at least one of a plurality of internal chambers residing entirely between the first layer of biocompatible material and the second layer of biocompatible material; and

g) Disposing at least one of a plurality of cover members covering the at least one of a plurality of openings, the at least one of a plurality of cover members having a first position which covers at least one of the plurality of openings and a second position which uncovers at least one of the plurality of openings.

15. The method according to claim 14, wherein the vacuum depositing steps further comprise at least one of physical vapor deposition and chemical vapor deposition.

16. The method according to claim 14, wherein step (g) is conducted before step (a) and step and further comprises the step of vacuum depositing the first layer of biocompatible material onto the plurality of cover members.

17. The method according to claim 14, further comprising the step of loading at least one bioactive agent into the at least one of a plurality of internal chambers.

18. The method according to claim 17, further comprising the step of selecting the at least one bioactive agent from the group of pharmacologically active antibiotic drugs, antiviral drugs, neoplastic agents, steroids, fibronectin, anti-clotting drugs, anti-platelet function drugs, drugs which prevent smooth muscle cell growth on inner surface wall of vessel, heparin, heparin fragments, aspirin, coumadin, tissue plasminogen activator, urokinase, hirudin, streptokinase, antiproliferative agents, antioxidants, antimetabolites, thromboxane inhibitors, non-steroidal and steroidal anti-inflammatory drugs, immunosuppresents, beta and calcium channel blockers, genetic materials including DNA and RNA fragments, complete expression genes, antibodies, lymphokines, growth factors, vascular endothelial growth factor, fibroblast growth factor, prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide, integrins, paclitaxel, taxol, rapamycin, rapamycin derivatives and analogues, sirolimus, rapamune, tacrolimus, dexamethasone, everolimus, ABT-578 and growth factors.

19. The method of claim 14, wherein at least one of the first layer of biocompatible material, the second layer of biocompatible material and the at least one of a plurality of cover members further comprise a thin metallic film.