Medical Implants and Methods of Making Medical Implants

• US 20110159069A1
• Filed: 12/28/2009
• Published: 06/30/2011
• Est. Priority Date: 12/26/2008
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Battelle Memorial Institute
• Inventors: Fulton, John L., McClain, James B., Yonker, Clement R., Shaw, Wendy J., Taylor, Doug, Tarasevich, Barbara J.
• Granted Patent: US 8,834,913 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2400/18 Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A medical implant device having a substrate with an oxidized surface and a silane derivative coating covalently bonded to the oxidized surface. A bioactive agent is covalently bonded to the silane derivative coating. An implantable stent device including a stent core having an oxidized surface with a layer of silane derivative covalently bonded thereto. A spacer layer comprising polyethylene glycol (PEG) is covalently bonded to the layer of silane derivative and a protein is covalently bonded to the PEG. A method of making a medical implant device including providing a substrate having a surface, oxidizing the surface and reacting with derivitized silane to form a silane coating covalently bonded to the surface. A bioactive agent is then covalently bonded to the silane coating. In particular instances, an additional coating of bio-absorbable polymer and/or pharmaceutical agent is deposited over the bioactive agent.

Claims

1. A medical implant device comprising:

a device substrate having a surface;

a silane derivative coating covalently bonded to the surface; and

a bioactive agent covalently bonded to the silane derivative coating.

2. The device of claim 1 wherein the bioactive agent is a small molecule.

3. The device of claim 2 wherein the small molecule has antithrombotic activity.

4. The device of claim 3 wherein the small molecule is heparin.

5. The device of claim 1 wherein the surface is oxidized.

6. The device of claim 1 further comprising a hetero-bifunctional polyethylene glycol spacer between the silane derivative coating and the bioactive agent, the spacer being covalently bonded to the coating an covalently bonded to the bioactive agent.

7. The device of claim 6 wherein the spacer is covalently bonded to the bioactive agent through a peptide bond and is covalently bonded to the coating through a peptide bond.

8. The device of claim 1 further comprising a bio-absorbable coating over the bioactive agent.

9. The device of claim 8 wherein the bio-absorbable coating comprises one or more polymers selected from the group consisting of poly(lactide-co-glycolide (PLGA);

poly(dl-lactide) (DLPLA);

poly(l-lactide) (LPLA);

polyglycolide (PGA);

poly(dioxanone) (PDO);

poly(glycolide-co-trimethylene carbonate) (PGA-TMC);

poly(l-lactide-co-glycolide) (PGA-LPLA);

poly(dl-lactide-co-glycolide) (PGA-DLPLA);

poly(l-lactide-co-dl-lactide) (LPLA-DLPLA); and

poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC)

10. The device of claim 8 wherein the bio-absorbable coating comprises at least one diffusible antistenotic drug.

11. The device of claim 1 wherein the substrate comprises one or more materials selected from the group consisting of stainless steel,

12. An implantable stent device comprising:

a stent core having a surface;

a layer of silane derivative covalently bonded to the surface;

a spacer layer comprising polyethelene glycol (PEG) covalently bonded to the layer of silane derivative; and

a protein covalently bonded to the PEG.

13. The device of claim 12 wherein the surface is oxidized.

14. The device of claim 12 wherein the PEG is derivatized and is bonded to the layer of silane derivative through a peptide bond and is bonded to the protein through a peptide bond.

15. The device of claim 12 wherein the protein comprises antithrombogenic activity.

16. The device of claim 12 wherein the pharmaceutical comprises heparin.

17. The device of claim 12 further comprising at least one coating layer over the heparin, wherein the at least one coating layer is bio-absorbable.

18. The device of claim 17 wherein the at least one coating layer comprises one or more antistenotic drugs.

19. The device of claim 17 wherein the at least one coating layer comprises one or more immunosuppressive drugs.

20. The device of claim 19 wherein the one or more immunosuppressive drugs is selected from the group consisting of rapamycin (sirolimus), 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′

-Hydroxymethyl)benzyl-rapamycin, 40-O[4′

-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′

-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′

-en-1′

-yl]-rapamycin, (2′

;

E,4′

S)-40-O-(4′

,5′

-Dihydroxypent-2′

-en-1′

-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin 4O—

O-(6-Hydroxy)hexyl-rapamycin 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin 4O—

O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 4O—

O-(2-Acetoxy)ethyl-rapamycin 4O—

O-(2-Nicotinoyloxy)ethyl-rapamycin, 4O—

O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 4O—

O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′

-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 4O—

O-(2-Nicotinamidoethyl)-rapamycin4O—

O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 4O—

O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 4O—

O-(2-Aminoethyl)-rapamycin, 4O—

O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-[2-(4′

,5′

-Dicarboethoxy-1′

,2′

,3′

-triazol-1′

-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

21. The device of claim 17 wherein the at least one coating layer comprises at least one layer of bio-absorbable polymer material.

22. An implantable medical device comprising:

a core implant device having an outer surface; and

a layer of derivatized silane over the surface and covalently bonded thereto.

23. The device of claim 22 wherein the outer surface comprises stainless steel.

24. The device of claim 22 further comprising at least one bioactive agent covalently bonded to the derivatized silane.

25. The device of claim 24 further comprising a polyethylene glycol-containing spacer between the bioactive agent and the derivatized silane.

26. The device of claim 24 wherein the bioactive agent is selected from the group consisting of biopolymers, pharmaceutical agents, synthetic polymers, amino acids and small organic molecules.

27. The device of claim 22 wherein the core implant device is selected from the group consisting of catheters, electrodes, stents, leads, pacemakers, cardioverter or defibrillator housings, artificial joints, screws, rods, ophthalmic implants, pins, bone plates, grafts, anastomotic devices, perivascular wraps, staples, shunts, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, vertebral disks, suture anchors, hemostatic barriers, clamps, plates, clips, vascular implants, tissue scaffolds, dressings, bone substitutes, intraluminal devices and vascular supports.

28. A method of making a medical implant device, comprising:

providing a device substrate having a surface;

reacting the surface with derivitized silane to form a silane coating over the surface, the coating being covalently bonded to the surface; and

covalently bonding a bioactive agent to the silane coating.

29. The method of claim 28 further comprising oxidizing the surface to produce an oxidized surface, and wherein the reacting the surface comprises reacting the oxidized surface.

30. The method of claim 28 wherein the bioactive agent has antithrombotic activity.

31. The method of claim 30 wherein the bioactive agent is heparin.

32. The method of claim 28 wherein the bioactive agent is a protein and wherein the covalently bonding occurs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to produce a peptide bond between the derivitized silane and the protein.

33. The method of claim 28 further comprising covalently bonding heterobifunctional polyethylene glycol to the derivitized silane surface and to the bioactive agent to form a spacer between the derivitized silane and the bioactive agent.

34. The method of claim 28 further comprising forming a bio-absorbable coating over the bioactive agent.

35. The method of claim 34 wherein the bio-absorbable coating comprises one or more polymers selected from the group consisting of poly(lactide-co-glycolide (PLGA);

poly(dl-lactide) (DLPLA);

poly(l-lactide) (LPLA);

polyglycolide (PGA);

poly(dioxanone) (PDO);

poly(glycolide-co-trimethylene carbonate) (PGA-TMC);

poly(l-lactide-co-glycolide) (PGA-LPLA);

poly(dl-lactide-co-glycolide) (PGA-DLPLA);

poly(l-lactide-co-dl-lactide) (LPLA-DLPLA); and

poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC).

36. The method of claim 34 wherein the bio-absorbable coating comprises at least one diffusible antistenotic drug.

37. A medical implant device comprising at least one silane derivative covalently bonded to a surface of the device and a bioactive agent covalently bonded to the at least one silane derivative.

38. The device of claim 37 wherein the surface comprises at least one oxidized site wherein the at least one silane derivative is covalently bonded to the at least one oxidized site.

39. The device of claim 37 wherein the surface comprises a plurality of oxidized sites wherein a plurality of silane derivative moieties are covalently bonded to the oxidized sites and a plurality of bioactive agent molecules are covalently linked to the silane derivative moieties thereby forming the surface a layer of silane derivative moieties covalently bonded to biological agent molecules.

40. The device of claim 37 wherein the surface is a polymer surface having a moiety forming a covalent bond with the silane derivative.

41. The device of claim 40 wherein the silane derivative and the polymer surface are coupled through an organosilane linkage.

42. The device of claim 41 wherein the organosilane linkage comprises a dialkoxysilane or a monoalkosysilane.

43. The device of claim 40 wherein the surface comprises a synthetic or a natural polymer.

44. The device of claim 43 wherein the surface comprises a natural polymer selected from cellulose, starch (amylose and amylopectin), proteins, silk, spider webs, polyhydroxyalkanoates, deoxyribonucleic acid (DNA), natural rubber, and polysacharides.

45. The device of claim 37 comprising a stent.

46. The device of claim 45 wherein the stent comprises a layer formed by biological agent covalently bonded to silane derivative moieties covalently bonded to a surface of the stent.

47. The device of claim 46 further comprising a plurality of layers that form a laminate coating on said stent;

wherein at least one of said layers comprises a bioabsorbable polymer and at least one of said layers comprises one or more active agents;

wherein at least a portion of the active agent is in crystalline form wherein the active agent is the same or different from the biological agent covalently bonded to the silane derivative moieties.

48. The device of claim 46 further comprising a plurality of layers that form a laminate coating on said stent;

wherein at least one of said layers comprises a bioabsorbable polymer and at least one of said layers comprises a pharmaceutical agent selected from rapamycin, a prodrug, a derivative, an analog, a hydrate, an ester, and a salt thereof;

wherein at least a portion of the pharmaceutical agent is in crystalline form.

49. The device of claim 48 wherein said coating exhibits an X-ray spectrum showing the presence of said pharmaceutical agent in crystalline form.

50. The device of claim 48 wherein presence of said pharmaceutical agent in crystalline form.

51. The device of claim 48 wherein said coating exhibits a Raman spectrum showing the presence of said pharmaceutical agent in crystalline form.

52. The device of claim 48 wherein said coating exhibits a Differential Scanning Calorimetry (DSC) curve showing the presence of said pharmaceutical agent in crystalline form.

53. The device of claim 48 wherein said coating exhibits Wide Angle X-ray Scattering (WAXS) spectrum showing the presence of said pharmaceutical agent in crystalline form.

54. The device of claim 48 wherein said coating exhibits a wide angle radiation scattering spectrum showing the presence of said pharmaceutical agent in crystalline form.

55. The device of claim 48 wherein said coating exhibits an Infra Red (IR) spectrum showing the presence of said pharmaceutical agent in crystalline form.

56. The device of claim 48 wherein the coating comprises at least two polymers wherein a first polymer is PLGA copolymer with a ratio of about 40:

60 to about 60;

40 and a second polymer is a PLGA copolymer with a ratio of about 70;

30 to about 90;

10.