Coated implantable medical device

• US 6,096,070 A
• Filed: 05/16/1996
• Issued: 08/01/2000
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Cook Medical Incorporated (Cook Group Incorporated)
• Original Assignee: Cook Incorporated (Cook Group Incorporated), MED Institute, Inc. (Cook Group Incorporated)
• Inventors: Bates, Brian L., Fearnot, Neal E., Kozma, Thomas G., Ragheb, Anthony O., Voorhees, William D. III
• Primary Examiner(s): Weiss, John G.
• Assistant Examiner(s): Cuddihy, Francis K.
• Application Number:
  US08/645,646
• Time in Patent Office: 1,538 Days
• Field of Search: 623/1, 623/11, 623/12, 604/53, 604/265, 424/423, 424/426, 514/772.2, 514/772.3, 514/822, 523/112, 523/113
• US Class Current: 623/1.39
• CPC Class Codes: A61F 2250/0068 the pharmaceutical product being in a reservoir
• CPC Class Codes: A61K 51/1282 Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/106 Inorganic materials other than carbon
• CPC Class Codes: A61L 29/146 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/088 Other specific inorganic materials not covered by A61L31/084 or A61L31/086
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/146 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/022 Metal or alloys
• CPC Class Codes: A61N 5/1002 Intraluminal radiation therapy
• CPC Class Codes: C08L 27/18 Homopolymers or copolymers or tetrafluoroethene
• CPC Class Codes: C08L 65/04 Polyxylenes
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 77/00 : Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain of polyhydrazides C08L79/06; of polyamideimides or polyamide acids C08L79/08; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 83/04 : Polysiloxanes

Abstract

A coated implantable medical device 10 includes a structure 12 adapted for introduction into the vascular system, esophagus, trachea, colon, biliary tract, or urinary tract; at least one layer 18 of a bioactive material posited on one surface of structure 12; and at least one porous layer 20 posited over the bioactive material layer 18 posited on one surface of structure (12) and the bioactive-material-free surface. Preferably, the structure 12 is a coronary stent. The porous layer 20 is comprised of a polymer applied preferably by vapor or plasma deposition and provides a controlled release of the bioactive material. It is particularly preferred that the polymer is a polyamide, parylene or a parylene derivative, which is deposited without solvents, heat or catalysts, merely by condensation of a monomer vapor. Also disclosed is the method of manufacture of the device 10, as well as a method of using it in medical treatments.

Claims

1. An implantable medical device (10), comprising:

a structure (12) adapted for introduction into a patient, the structure (12) having at least one surface and being composed of a base material (14);

at least one layer (18) of a first bioactive material posited on one surface of the structure (12); and

at least one porous layer (20) posited over the bioactive material layer (18), wherein said at least one porous layer (20) is composed of a polymer and said polymer provides for a controlled release of the bioactive material through said at least one porous layer.

2. The device (10) of claim 1, wherein the at least one porous layer (20) is one polymerized from a catalyst-free monomer vapor.

3. The device (10) of claim 1, wherein the polymer is selected from the group consisting of a polyamide, polymers of parylene or derivatives thereof, poly(ethylene oxide), poly(ethylene glycol), poly(propylene oxide), silicone based polymers, polymers of methane, tetrafluoroethylene or tetramethyldisiloxane or a polymer derived from photopolymerizeable monomers.

4. The device (10) of claim 3, wherein the thickness of the at least one porous layer (20) is about 5,000 to 250,000 Å

.

5. The device (10) of claim 1, further comprising at least one additional coating layer (16) between the structure (12) and the at least one bioactive material layer (18).

8. The device (10) of claim 1, wherein the structure (12) is configured as a vascular stent.

9. The device (10) of claim 1, wherein the structure (12) is configured as at least one of:

a stent, a vascular or other graft, a vascular or other graft in combination with a stent, heart valve, an orthopedic device, appliance, implant or replacement, or portion thereof;

or a portion of any of these.

10. The device (10) of claim 1, wherein the base material (14) is biocompatible.

11. The device (10) of claim 10, wherein the base material (14) of the structure (12) is selected from the group consisting of stainless steel, tantalum, titanium, Nitinol, gold, platinum, inconel, iridium, silver, tungsten, or another biocompatible metal, or alloys of any of these;

carbon or carbon fiber;

cellulose acetate, cellulose nitrate, silicone, polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or another biocompatible polymeric material, or mixtures or copolymers thereof;

polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxy-butyrate valerate or another biodegradable polymer, or mixtures or copolymers of these;

a protein, an extracellular matrix component, collagen, fibrin or another biologic agent;

or a mixture thereof.

12. The device (10) of claim 1, wherein the bioactive material includes at least one of:

heparin, covalent heparin, or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent, or mixtures thereof;

urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof;

a fibrinolytic agent;

a vasospasm inhibitor;

a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter or another vasodilator;

an antimicrobial agent or antibiotic;

aspirin, ticlopidine, a glycoprotein IIb/IIIa inhibitor or another inhibitor of surface glycoprotein receptors, or another antiplatelet agent;

colchicine or another antimitotic, or another microtubule inhibitor, dimethyl sulfoxide (DMSO), a retinoid or another antisecretory agent;

cytochalasin or another actin inhibitor;

or a remodeling inhibitor;

deoxyribonucleic acid, an antisense nucleotide or another agent for molecular genetic intervention;

methotrexate or another antimetabolite or antiproliferative agent;

tamoxifen citrate, Taxol®

or derivatives thereof, or other anti-cancer chemotherapeutic agents;

dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or another dexamethasone derivative, or another anti-inflammatory steroid or non-steroidal anti-inflammatory agent;

cyclosporin or another immunosuppressive agent;

trapidal (a PDGF antagonist), angiogenin, angiopeptin (a growth hormone antagonist), a growth factor or an anti-growth factor antibody, or another growth factor antagonist;

dopamine, bromocriptine mesylate, pergolide mesylate or another dopamine agonist;

⁶⁰ Co, ¹⁹² Ir, ³² P, ¹¹¹ In, ⁹⁰ Y, ^99m Tc or another radiotherapeutic agent;

iodine-containing compounds, barium-containing compounds, gold, tantalum, platinum, tungsten or another heavy metal functioning as a radiopaque agent;

a peptide, a protein, an enzyme, an extracellular matrix component, a cellular component or another biologic agent;

captopril, enalapril or another angiotensin converting enzyme (ACE) inhibitor;

ascorbic acid, alpha tocopherol, superoxide dismutase, deferoxamine, a 21-amino steroid (lasaroid) or another free radical scavenger, iron chelator or antioxidant;

a ¹⁴ C-, ³ H-, ¹³¹ I-, ³² P- or ³⁶ S-radiolabelled form or other radiolabelled form of any of the foregoing;

estrogen or another sex hormone;

AZT or other antipolymerases;

acyclovir, famciclovir, rimantadine hydrochloride, ganciclovir sodium or other antiviral agents;

5-aminolevulinic acid, meta-tetrahydroxyphenylchlorin, hexadecafluoro zinc phthalocyanine, tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic therapy agents;

an IgG2 Kappa antibody against Pseudomonas aeruginosa exotoxin A and reactive with A431 epidermoid carcinoma cells, monoclonal antibody against the noradrenergic enzyme dopamine beta-hydroxylase conjugated to saporin or other antibody targeted therapy agents;

gene therapy agents; and

enalapril and other prodrugs, or a mixture of any of these.

13. The device (10) of claim 1, wherein the at least one layer (18) of bioactive material comprise about 0.01 to 4 mg of the bioactive material per cm² of the gross surface area of the structure (12).

14. The device (10) of claim 1, wherein the structure (12) has a plurality of surfaces, and different bioactive materials are posited on the surfaces of the structure (12).

15. The device (10) of claim 1, wherein a different and second bioactive material is posited on the porous layer (20) and forms an outermost layer for the structure (20).

16. The device of claim 15, wherein a different and third bioactive material is posited on a bioactive-material-free surface of the structure (12), the at least one porous layer (20) being posited over the first bioactive material and a third bioactive material;

and wherein the second bioactive material forming the outermost layer is covalent heparin bound to the at least one porous layer (20).

17. The device of claim 1 wherein the structure (12) comprises either a single bioactive material on one surface of said structure (12) or different bioactive materials on the different surfaces of said structure (12) with a the at least one porous layer (20) over said single first bioactive material or said different bioactive materials and said second bioactive material forms the outermost layer over said at least one porous layer (12).

18. The device (10) of claim 1, wherein the structure (12) has a plurality of different surfaces, and wherein individual ones of a plurality of layers of different bioactive materials are posited on the different surfaces of the structure (12), wherein a same bioactive material is not posited on the different surfaces of the structure (12) within the same individual one of the plurality of layers of bioactive material, and wherein either a porous layer or a bioactive material layer may form an outermost layer for the structure (12).

19. The device (10) of claim 1 wherein said bioactive material (18) is posited on said one surface of structure (12) in a geometric pattern.

20. The device (10) of claim 19 wherein said device is a stent and said bioactive material (18) is posited on said at least one surface of the stent in a discontinuous geometric pattern.

21. The device (10) of claim 20 wherein said bioactive material (18) is posited on said at least one surface of the stent in a pattern of parallel lines or wherein said stent is a vascular stent in its flattened state wherein said stent having arms attached and extending from a spine and wherein said arms having tips at a point furthest from the attachment of said arms to said spine, wherein said bioactive material is not posited on the tips of the arms of said stent.

22. The device of claim 1 wherein two or more different bioactive materials (18) are posited on said at least one surface of the structure (12).

23. The device (10) of claim 22 wherein the two or more bioactive materials (18) are posited on adjacent areas of the said at least one surface of the structure (12).

24. The device (10) of claim 1, further comprising a connector (26) securing the at least one porous layer (20) to the base material (14) of the structure (12).

32. The device (10) of claim 5, wherein at least one additional coating layer is less porous than, but composed of a different polymer as, the at least one porous layer (20).

6. An implantable medical device (10), comprising:

a structure (12) adapted for introduction into a patient, the structure (12) having at least one surface and being comprised of a base material (14);

at least one layer (18) of a bioactive material posited on the at least one surface of the structure (12);

at least one porous layer (20) posited over the bioactive material layer (18), wherein the at least one porous layer (20) is comprised of a polymer and said polymer provides for a controlled release of the bioactive material therethrough; and

at least one additional coating layer (16) between the structure (12) and the at least one bioactive material layer (18);

wherein the at least one additional coating layer (16) is less porous than, but comprised of the same polymer as, the at least one porous layer (20).

7. The device (10) of claim 6, wherein the polymer is selected from the group consisting of polyamide, polymers of parylene or derivatives thereof, or a polymer derived from photopolymerizable monomers of bisphenol A diglycidyl ether and acrylic acid or methacrylic acid, and the at least one additional coating layer (16) is about 50,000 to 500,000 Å

thick.

25. An implantable medical device, comprising:

a structure adapted for introduction into a patient, the structure having at least one surface and being comprised of a base material;

wherein the base material comprises apertures within a surface of the base material and containing at least one bioactive material within said apertures;

wherein at least one porous layer is posited over said base material and said at least one bioactive material contained within said apertures; and

wherein said at least one porous layer is comprised of a polymer and said polymer provides for a controlled release of the at least one bioactive material.

26. The medical device of claim 25 wherein said apertures are selected from the group consisting essentially of holes, slots, grooves or wells and may have a sectional shape of a half circle, a letter V or a truncated square.

27. The medical device of claim 26 wherein said holes, slots, grooves or wells may be formed by etching using a photo resist pattern;

by cutting with laser or EBM;

or by stamping.

28. The medical device of claim 27 wherein different bioactive materials are contained within the holes, grooves, slots or wells.

29. The medical device of claim 28 wherein the at least one bioactive material is selected from the group consisting essentially of heparin, covalent heparin or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent, or mixtures thereof;

urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof;

a fibrinolytic agent;

a vasospasm inhibitor;

a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter or another vasodilator;

an antimicrobial agent or antibiotic;

aspirin, ticlopidine, a glycoprotein IIb/IIIa inhibitor or another inhibitor of surface glycoprotein receptors, or another antiplatelet agent;

colchicine or another antimitotic, or another microtubule inhibitor, dimethylsulfoxide (DMSO), a retinoid or another antisecretory agent;

cytochalasin or another actin inhibitor;

or a remodeling inhibitor;

deoxyribonucleic acid, an antisense nucleotide or another agent for molecular genetic intervention;

methotrexate or another antimetabolite or antiproliferative agent;

tamoxifen citrate, Taxol®

or derivatives thereof, or other anti-cancer chemotherapeutic agents;

dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or another dexamethasone derivative, or another anti-inflammatory steroid or non-steroidal anti-inflammatory agent;

cyclosporin or another immunosuppressive agent;

tripodal (aPDGF antagonist), angiopeptin (a growth hormone antagonist), angiogenin or other growth factors, or an anti-growth factor antibody, or another growth factor antagonist;

dopamine, bromocriptine mesylate, pergolide mesylate or another dopamine agonist;

⁶⁰ Co, ¹⁹² Ir, ³² P, ¹¹¹ In, ⁹⁰ Y, ^99m Tc or another radiotherapeutic agent;

iodine-containing compounds, barium-containing compounds, gold, tantalum, platinum, tungsten or another heavy metal functioning as a radiopaque agent;

a peptide, a protein, an enzyme, an extracellular matrix component, a cellular component or another biologic agent;

captopril, enalapril or another angiotensin converting enzyme (ACE) inhibitor;

ascorbic acid, alpha tocopherol, superoxide dismutase, deferoxamine, a 21-amino steroid (lasaroid) or another free radical scavenger, iron chelator or antioxidant;

a ¹⁴ C-, ³ H-, ¹³¹ I-, ³² P- or ³⁶ S-radiolabelled form or other radiolabelled form of any of the foregoing;

estrogen or another sex hormone;

AZT or other antipolymerases;

acyclovir, famciclovir, rimantadine hydrochloride, ganciclovir sodium or other antiviral agents;

5-aminolevulinic acid, meta-tetrahydroxyphenylchlorin, hexadecaflouoro zinc phthalocyanine, tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic therapy agents;

an IgG2 Kappa antibody against Pseudomonas aeruginosa exotoxin A and reactive with A431 epidermoid carcinoma cells, monoclonal antibody against the noradrenergic enzyme dopamine betahydroxylase conjugated to saporin or other antibody target therapy agents;

enalapril or other prodrugs; and

gene therapy agents, or a mixture of any of these.

33. The medical device of claim 26 wherein said apertures have a cross sectional shape selected from the group consisting essentially of a half circle, a letter V, or a truncated square.

30. An implantable medical device comprising:

a structure adapted for introduction into a patient, the structure having at least one surface and being comprised of a base material;

wherein the base material comprises apertures within a surface of the base material and having at least one bioactive material within said apertures;

wherein at least one porous layer is posited over said base material and said at least one bioactive material is contained within said apertures; and

wherein said at least one porous, layer is comprised of a polymer and said polymer provides for a controlled release of said at least one bioactive material;

wherein said apertures are selected from the group consisting of holes, slots, grooves or wells and may have a sectional shape of a half circle, a letter V or a truncated square; and

wherein the base material comprises a substantially non-porous coating, and said at least one porous layer overlies the holes, grooves, slots or wells containing said at least one bioactive material.

31. The medical device of claim 30 wherein said device further comprises layers of bioactive materials and porous layer coatings.